Pharmaceutical compositions of drugs and neutralized acidic polymers

ABSTRACT

Pharmaceutical compositions comprised of low-solubility and/or acid-sensitive drugs and neutralized acidic polymers are disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. application Ser. No.11/213,118, filed Aug. 26, 2005, which is a Continuation of U.S.application Ser. No. 10/175,566 filed Jun. 17, 2002, which claims thebenefit of priority of U.S. provisional Patent Application Ser. No.60/300,256 filed Jun. 22, 2001.

BACKGROUND OF THE INVENTION

This invention relates to pharmaceutical compositions of drugs andneutralized acidic polymers that provide improved chemical and physicalproperties.

It is often desired to improve the aqueous concentration andbioavailability of a poorly soluble drug. Improving either thedissolution rate of the drug or the maximum concentration of drugachieved in an aqueous use environment can enhance the absorption andhence bioavailability of the drug. Further, decreasing the rate at whichthe concentration of drug falls from the maximum concentration to theequilibrium concentration may also improve bioavailability.

Forming a dispersion of a drug and polymer may enhance drugconcentration in a use environment. For example, Curatolo, et al., EP 0901 786 A2 disclose forming pharmaceutical spray dried amorphousdispersions of sparingly soluble drugs and the polymer hydroxypropylmethyl cellulose acetate succinate. The spray dried dispersionsdisclosed in Curatolo et al. provide superior aqueous concentrationrelative to dispersions formed from other methods and relative to thecrystalline drug alone.

Similarly, others have recognized the enhancement in aqueousconcentration afforded by dispersing a drug in a polymer. Nakamichi, etal., U.S. Pat. No. 5,456,923 disclose solid dispersions formed bytwin-screw extrusion of low solubility drugs and various polymers,including hydroxypropyl methyl cellulose acetate succinate andhydroxypropyl methyl cellulose phalthalate, among others.

Nevertheless, dispersing a low-solubility drug in a polymer continues topresent challenges. One problem encountered is that the drug and/ordispersion may not be physically stable. The amorphous drug may separatefrom the dispersion polymer, either as a drug-enriched amorphous phaseor as a crystalline phase, thereby decreasing the concentrationenhancement provided by the dispersion.

The inventors have also found that for some drugs, the drugs are notchemically stable within some dispersion polymers. In particular, theinventors have observed that for dispersions containing certain drugsand acidic polymers, the drug chemically degrades in the dispersion overtime, resulting in a loss of potency and an increase in unwantedimpurities.

Anderson et al., U.S. Pat. No. 5,508,276 disclose an enteric duloxetinepellet comprising a core consisting of duloxetine, an optionalseparating layer, and an enteric layer comprising hydroxypropyl methylcellulose acetate succinate (HPMCAS). The HPMCAS may be partiallyneutralized to form a smooth, coherent enteric layer.

Hodges et al., U.S. Pat. No. 5,225,202 disclose an enteric coatedcomposition which includes a medicament which is sensitive to a low pHenvironment of less than 3. The composition has an enteric coatingformed of neutralized hydroxypropylmethyl cellulose acetate phthalate,plasticizer and anti-adherent.

Takeuchi, et al. Spherical Solid Dispersion Containing AmorphousTolbutamide Embedded in Enteric Coating Polymers or Colloidal SilicaPrepared by Spray-Drying Technique, Chem. Pharm. Bull. Vol. 35, pp.3800-3806 (1987), disclose solid amorphous dispersions of tolbutamideand an enteric polymer. The drug and polymer are initially dissolved ina 2 wt % ammonia solution forming ammonium salts, but reverted to theiroriginal forms during the spray-drying process.

Nevertheless, there is still a need for pharmaceutical compositions oflow-solubility drugs and polymers that have improved physical stability,chemical stability, and/or improved concentration enhancement andbioavailability.

BRIEF SUMMARY OF INVENTION

The present invention provides, in one aspect, pharmaceuticalcompositions comprising a mixture of a low-solubility drug in asolubility-improved form and a neutralized acidic enteric polymer,wherein said composition provides enhanced concentration of saidlow-solubility drug in a use environment relative to a controlcomposition, wherein said control composition comprises an equivalentquantity of said low-solubility drug and is free from aconcentration-enhancing polymer.

In a preferred embodiment, the mixture is a solid amorphous dispersionof said low-solubility drug and said neutralized acidic enteric polymer.

In another preferred embodiment, the degree of neutralization of saidneutralized acidic enteric polymer is at least 0.1, preferably at least0.5, more preferably at least 0.9, more preferably about 1.

In another preferred embodiment, the neutralized acidic enteric polymercomprises a counterion selected from the group consisting of sodium,potassium, calcium, magnesium, aluminum, ammonium, iron, and amine.

In another preferred embodiment, the neutralized acidic enteric polymercomprises a blend of polymers.

In another preferred embodiment, the neutralized acidic enteric polymeris cellulosic, preferably selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate,hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatephthalate, cellulose acetate phthalate, methyl cellulose acetatephthalate, ethyl cellulose acetate phthalate, hydroxypropyl celluloseacetate phthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylmethyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate, and carboxymethyl ethyl cellulose.More preferably, the neutralized acidic enteric polymer is selected fromthe group consisting of hydroxypropyl methyl cellulose acetatesuccinate, cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methyl cellulose phthalate, and carboxymethyl ethylcellulose.

In another preferred embodiment, the neutralized acidic enteric polymeris a neutralized form of a polymer selected from the group consisting ofcarboxylic acid functionalized vinyl polymers, carboxylic acidfunctionalized polymethacrylates, and carboxylic acid functionalizedpolyacrylates.

In another preferred embodiment, the neutralized acidic enteric polymerhas a glass transition temperature of at least 40° C.

In another preferred embodiment, the neutralized acidic enteric polymeris ionically crosslinked, preferably the neutralized acidic entericpolymer is ionically crosslinked with a multivalent cationic species.Preferably, the multivalent cationic species is selected from the groupconsisting of calcium, magnesium, aluminum, iron (II), iron (III), and adiamine.

In another preferred embodiment, the composition further comprises abase. Preferably, the base is selected from the group consisting ofsodium hydroxide, potassium hydroxide, calcium hydroxide, magnesiumhydroxide, aluminum hydroxide, ammonia, ammonium hydroxide, ammoniumacetate, sodium acetate, potassium acetate, calcium acetate, magnesiumacetate, sodium citrate, trisodium phosphate, disodium phosphate,ethylene diamine, monoethanol amine, diethanol amine, triethanolamine,potassium citrate, sodium carbonate, sodium bicarbonate, sodium acetate,amine-functional polyacrylates, and sodium polyacrylic acid. Preferably,the base comprises at least 5 wt % of said composition.

In another preferred embodiment, the drug has a solubility in aqueoussolution in the absence of said polymer of less than 1 mg/ml, preferablyless than 0.1 mg/ml, at any pH of from about 1 to about 8.

In another preferred embodiment, the drug has adose-to-aqueous-solubility ratio of at least 10 ml.

In another preferred embodiment, the low-solubility drug isacid-sensitive. Preferably, the acid-sensitive drug has at least onefunctional group selected from the group consisting of sulfonyl ureas,hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxy ureas,esters, and amides. Preferably, the acid-sensitive drug is selected fromthe group consisting of quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; and progabide.

In another preferred embodiment, the composition provides improvedchemical stability of said drug relative to a second controlcomposition, wherein said second control composition comprises adispersion of an equivalent quantity of said low-solubility drug and anunneutralized form of said neutralized acidic enteric polymer.Preferably, the composition provides a relative degree of improvement instability for said drug of at least 1.25, preferably at least 3, morepreferably at least 10, when stored at 40° C. and 75% relative humidity.

In another preferred embodiment, the maximum concentration of said drugin said use environment is at least 1.25-fold that of said controlcomposition.

In another preferred embodiment, the neutralized acidic enteric polymeris present in a sufficient amount so that said composition provides insaid use environment an area under the concentration versus time curvefor any period of at least 90 minutes between the time of introductioninto the use environment and about 270 minutes following introduction tosaid use environment that is at least 1.25-fold, preferably at least2-fold, that of said control composition.

In another preferred embodiment, the neutralized acidic enteric polymeris present in a sufficient amount so that said composition provides arelative bioavailability that is at least 1.25 relative to said controlcomposition.

In another preferred embodiment, the composition further comprises asecond concentration-enhancing polymer.

In a second aspect, the present invention relates to pharmaceuticalcompositions comprising a solid amorphous dispersion of anacid-sensitive drug and a neutralized acidic dispersion polymer, whereinsaid composition provides improved chemical stability of said drugrelative to a control composition comprised of a dispersion of anequivalent quantity of said drug and an unneutralized form of saidacidic polymer. Preferably, the degree of neutralization of saidneutralized acidic polymer is at least 0.1, more preferably at least0.5, more preferably at least 0.9, more preferably at least 1.

In another preferred embodiment, the neutralized acidic dispersionpolymer has a counterion selected from the group consisting of sodium,potassium, calcium, magnesium, aluminum, ammonium, iron, and amine.

In another preferred embodiment, the neutralized acidic dispersionpolymer comprises a blend of polymers.

In another preferred embodiment, the neutralized acidic dispersionpolymer is cellulosic. Preferably, neutralized acidic dispersion polymeris a neutralized form of a polymer selected from the group consisting ofhydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate,hydroxyethyl methyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, hydroxyethyl methylcellulose acetate succinate, hydroxyethyl methyl cellulose acetatephthalate, cellulose acetate phthalate, methyl cellulose acetatephthalate, ethyl cellulose acetate phthalate, hydroxypropyl celluloseacetate phthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylmethyl cellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, ethylpicolinic acid cellulose acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose, and carboxy ethyl cellulose. More preferably, theneutralized acidic polymer is a neutralized form of a polymer selectedfrom the group consisting of hydroxy propyl methyl cellulose acetatesuccinate, cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methyl cellulose phthalate, carboxymethyl cellulose,carboxymethyl ethyl cellulose.

In another preferred embodiment, the neutralized acidic dispersionpolymer is a neutralized form of a polymer selected from the groupconsisting of carboxylic acid functionalized vinyl polymers, carboxylicacid functionalized polymethacrylates, and carboxylic acidfunctionalized polyacrylates.

In another preferred embodiment, the neutralized acidic dispersionpolymer has a glass transition temperature of at least 40° C.

In another preferred embodiment, the composition further comprises abase. Preferably, the composition comprises a physical mixture of saiddispersion and said base. Preferably, the base is selected from thegroup consisting of sodium hydroxide, potassium hydroxide, calciumhydroxide, magnesium hydroxide, aluminum hydroxide, ammonia, ammoniumhydroxide, ammonium acetate, sodium acetate, potassium acetate, calciumacetate, magnesium acetate, sodium citrate, trisodium phosphate,disodium phosphate, ethylene diamine, monoethanol amine, diethanolamine, triethanolamine, potassium citrate, sodium carbonate, sodiumbicarbonate, sodium acetate, amine-functional polyacrylates, and sodiumpolyacrylic acid.

In another preferred embodiment, the dispersion has a pH greater than 5.

In another preferred embodiment, the acid-sensitive drug has asolubility in aqueous solution in the absence of said neutralized acidicpolymer of less than 1 mg/ml, preferably less than 0.1 mg/ml, at any pHof from about 1 to about 8.

In another preferred embodiment, the acid-sensitive drug has adose-to-aqueous-solubility ratio of at least 10 ml.

In another preferred embodiment, the acid-sensitive drug has at leastone functional group selected from the group consisting of sulfonylureas, hydroxamic acids, hydroxy amides, carbamates, acetals, hydroxyureas, esters, and amides.

In another preferred embodiment, the acid-sensitive drug is selectedfrom the group consisting of quinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amide;quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide;(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; and progabide.

In another preferred embodiment, the composition provides a relativedegree of improvement for said drug of at least 1.25, preferably atleast 3, more preferably at least 10, when stored at 40° C. and 75%relative humidity.

In another preferred embodiment, the neutralized acidic polymer isconcentration-enhancing and present in a sufficient amount to provide amaximum concentration of said acid-sensitive drug in a use environmentthat is at least 1.25-fold that of a second control composition, saidsecond control composition comprising an equivalent quantity of saidacid-sensitive drug but free from a concentration-enhancing polymer.

In another preferred embodiment, the neutralized acidic polymer isconcentration-enhancing and is present in a sufficient amount so thatsaid composition provides in a use environment an area under theconcentration versus time curve for any period of at least 90 minutesbetween the time of introduction into the use environment and about 270minutes following introduction to the use environment that is at least1.25-fold, preferably at least 2-fold, that of a control composition,said second control composition comprising an equivalent quantity ofsaid acid-sensitive drug and free from a concentration-enhancingpolymer.

In another preferred embodiment, the neutralized acidic polymer isconcentration-enhancing and is present in an amount so that saiddispersion provides a relative bioavailability that is at least 1.25relative to a second control composition, said second controlcomposition comprising an equivalent quantity of said acid-sensitivedrug and free from a concentration-enhancing polymer.

In another preferred embodiment, the composition further comprises asecond polymer, said second polymer being concentration-enhancing.

In a third aspect, the present invention relates to methods for treatinga condition in an animal comprising administering to an animal in needof such treatment a therapeutic amount of the above-describedcompositions.

In a fourth aspect, the present invention relates to methods for forminga solid pharmaceutical composition, comprising the steps of: (a)neutralizing an acidic enteric polymer to form a neutralized acidicenteric polymer; and (b) combining a low-solubility drug with saidneutralized acidic enteric polymer, said neutralized acidic entericpolymer being present in a sufficient amount in said composition so asto be concentration-enhancing.

In a preferred embodiment, step (a) further comprises the steps of (1)dissolving said acidic enteric polymer in a solvent to form a solutionand (2) adding a base to said solution.

In another preferred embodiment, the low-solubility drug and said acidicenteric polymer are both dissolved in a common solvent to form asolution. Preferably, the method further comprises the step of adding abase to said solution. Preferably, the solvent is removed from saidsolution forming a solid amorphous dispersion.

In another preferred embodiment, the acidic enteric polymer isneutralized prior to being combined with said drug. Alternatively, theacidic enteric polymer is combined with said drug prior to neutralizingsaid acidic enteric polymer.

In another preferred embodiment, the drug and said neutralized acidicenteric polymer are combined to form a solid amorphous dispersion.

In another preferred embodiment, the drug at least partially neutralizessaid polymer.

The fifth aspect of the present invention relates to methods for forminga pharmaceutical composition, comprising the steps of: (a) neutralizingan acidic polymer to form a neutralized acidic polymer; and (b) forminga solid amorphous dispersion of an acid-sensitive drug and saidneutralized acidic polymer, said dispersion providing improved chemicalstability relative to a control composition comprised of an equivalentquantity of said acid-sensitive drug and the unneutralized form of saidneutralized acidic polymer.

In a preferred embodiment, the acidic polymer is neutralized prior tobeing combined with said acid-sensitive drug. Alternatively, the acidicpolymer and said drug are combined prior to neutralizing said acidicpolymer.

In a sixth aspect, the present invention relates to methods for forminga pharmaceutical composition, comprising the steps of: (a) forming asolid amorphous dispersion of an acid-sensitive drug and an acidicpolymer; and (b) neutralizing said acidic polymer after forming saiddispersion.

In a preferred embodiment, the acidic polymer is neutralized bycombining said dispersion with a base.

The present inventors have found that neutralized acidic entericpolymers provide several advantages over conventional unneutralizedacidic enteric polymers. Compositions of neutralized acidic entericpolymers and drugs tend to be more physically and chemically stable thanunneutralized polymers. Thus, the compositions may provide improveduniformity of drug potency and concentration enhancement whenadministered to a use environment after being stored under typicalambient storage conditions. In addition, neutralized acidic entericpolymers also may provide greater concentration enhancement and fasterdissolution. This may lead to improved bioavailability of thelow-solubility drug.

Often, acidic dispersion polymers are preferred for use withlow-solubility drugs because such polymers often provide greaterconcentration enhancement than that provided by non-acidic polymers.However, the inventors have recognized that a problem with formingdispersions of acid-sensitive drugs is that for some dispersions, thedrug does not remain chemically stable in the dispersion over time. Theinventors have found that acid-sensitive drugs dispersed in an acidicpolymer, such as hydroxypropyl methyl cellulose acetate succinate orcellulose acetate phthalate, both of which have carboxylic acidfunctional groups, have a tendency to chemically degrade over time. Itis believed that the presence of acidic ionic groups on the acidicpolymer either catalyze degradation of the drug or react directly withthe drug. Such reactions may occur due to the acidic environment inducedby the presence of the carboxylic acid groups (for example, a highhydrogen ion activity) or by direct interaction of the drug and thecarboxylic acid groups.

In any event, regardless of the particular degradation mechanism, theinventors have substantially reduced, if not eliminated the problem, byforming dispersions using neutralized forms of the otherwise acidicdispersion polymer. Thus, the present invention is able to realize theadvantages of forming dispersions of low-solubility, acid-sensitivedrugs by improving the chemical stability of the acid-sensitive drug inthe dispersion, while retaining the superior concentration enhancementprovided by the use of acidic dispersion polymers.

As described more fully below, the term “use environment” may refer toeither the in vivo environment of the gastrointestinal (GI) tract of ananimal, particularly a human, or the in vitro environment of a testsolution, such as phosphate buffered saline (PBS) or model fastedduodenal (MFD) solution.

The compositions of the present invention may be dosed in a variety ofdosage forms, including both immediate release and controlled releasedosage forms, the latter including both delayed and sustained releaseforms. The composition may include blends of polymers.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical compositions of the present invention comprisemixtures of a drug and a neutralized acidic polymer. The presentinvention finds utility anytime it is desired to improve the aqueousconcentration of a low-solubility drug, and finds particular utilitywhen the drug is acid-sensitive.

In a first embodiment of the invention, the composition comprises amixture of a low-solubility drug and a neutralized acidic entericpolymer. Compositions formed from neutralized acidic enteric polymersprovide improved physical and/or chemical drug stability,concentration-enhancement and dissolution properties relative to theunneutralized form of the acidic enteric polymer. Thus, the inventionwill find utility for any low-solubility drug and/or composition whichmay benefit from improved physical or chemical stability, improvedconcentration enhancement, and/or improved dissolution.

In the first embodiment of the invention the drug and neutralized acidicenteric polymer may be mixed in any conventional fashion so as toachieve a relatively uniform mixture. The drug and polymer may exist indrug-rich and polymer-rich domains, may exist together as a homogeneoussolid solution or in some state in between. The mixture may be formed byany conventional method, such as by blending, milling, or granulating. Apreferred mixture is a molecular dispersion.

In a second embodiment, a composition comprises a dispersion of anacid-sensitive drug and a neutralized acidic polymer. Dispersions of thepresent invention formed from neutralized acidic polymers improve thechemical stability of acid-sensitive drugs relative to dispersions ofthe same drug in the unneutralized acidic form of the polymer. Thedispersions of the second embodiment simultaneously provide enhancedchemical stability and enhanced drug concentration in a use environmentand, in turn, enhanced bioavailability. The dispersions may be used toprevent degradation of the drug due to interactions with dispersionpolymers, other acidic dispersion species, or other acidic excipientspresent in the composition.

Suitable drugs, particularly acid-sensitive drugs, acidic polymers andmethods for making the various compositions of low-solubility drug andacidic polymer are discussed in more detail below.

The Drug

The term “drug” is conventional, denoting a compound having beneficialprophylactic and/or therapeutic properties when administered to ananimal, especially humans. The drug is a “low-solubility drug,” meaningthat the drug may be either “substantially water-insoluble,” which meansthat the drug has a minimum aqueous solubility at physiologicallyrelevant pH (e.g., pH 1-8) of less than 0.01 mg/mL, “sparinglywater-soluble,” that is, has an aqueous solubility up to about 1 to 2mg/mL, or even low to moderate aqueous-solubility, having anaqueous-solubility from about 1 mg/mL to as high as about 20 to 40mg/mL. In general, it may be said that the drug has a dose-to-aqueoussolubility ratio greater than 10 mL, and more typically greater than 100mL, where the drug solubility (mg/mL) is the minimum value observed inany physiologically relevant aqueous solution (e.g., those with pHvalues between 1 and 8) including USP simulated gastric and intestinalbuffers, and the dose is in mg. The dose-to-aqueous-solubility-ratio maybe determined by simply dividing the dose (in mg) by the aqueoussolubility (in mg/mL).

The drug must be formulated in a manner so as to be capable of providingan initially enhanced drug concentration that is greater than theequilibrium concentration of the drug in the use environment (i.e., asuper-saturated drug concentration). It is believed that the polymers ofthe present invention do not have the ability to enhance the solubilityof the drug in the use environment. Instead, the polymers inhibit orretard the rate at which the initially enhanced concentration of drugdecreases to the equilibrium concentration of drug. The drug may beformulated as a solid amorphous dispersion of drug and polymer such thatthe dispersion provides an initial concentration of drug in the useenvironment that is greater than the equilibrium concentration of drugin the use environment.

Alternatively, the drug may be formulated in a solubility-improved form.Solubility-improved forms include crystal and highly soluble salt formsof the drug, high-energy crystalline forms of the drug (such aspolymorphs), amorphous drug, a mixture of the drug and a solubilizingagent, and drug predissolved in a solution. Examples of suchsolubility-improved forms are more fully described in commonly assignedpending patent application titled Pharmaceutical Compositions ProvidingEnhanced Drug Concentrations, Ser. No. 09/742,785, filed Dec. 20, 2000,which claims priority to provisional patent application Ser. No.60/171,841, filed Dec. 23, 1999, the disclosure of which is incorporatedby reference.

As yet another alternative, the drug may be a basic drug which dissolvesreadily in gastric solution. Upon entering intestinal solution, a drugconcentration that exceeds the equilibrium concentration of drug in theintestinal solution may be temporarily achieved. Such basic drugs aredisclosed in commonly assigned pending patent application Ser. No.09/495,438, filed Jan. 31, 2000, which claims priority to provisionalpatent application Ser. No. 60/119,283, filed Feb. 9, 1999, the relevantdisclosure of which is herein incorporated by reference.

Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-depressants, antiviral agents,anti-artheriosclerotic agents, glycogen phosphorylase inhibitors, andcholesterol ester transfer protein inhibitors.

Specific examples of the above and other classes of drugs andtherapeutic agents deliverable by the invention are set forth below, byway of example only. Each named drug should be understood to include theneutral form of the drug, pharmaceutically acceptable salts, as well asprodrugs. Specific examples of antihypertensives include prazosin,nifedipine, amlodipine besylate, trimazosin and doxazosin; specificexamples of a blood glucose-lowering agent are glipizide andchlorpropamide; a specific example of an anti-impotence agent issildenafil and sildenafil citrate; specific examples of antineoplasticsinclude chlorambucil, lomustine and echinomycin; a specific example ofan imidazole-type antineoplastic is tubulazole; a specific example of ananti-hypercholesterolemic is atorvastatin calcium; specific examples ofanxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride;specific examples of anti-inflammatory agents include betamethasone,prednisolone, aspirin, piroxicam, valdecoxib, carprofen, celecoxib,flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hyroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinol and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include carbenicillin indanylsodium,bacampicillin hydrochloride, troleandomycin, doxycyline hyclate,ampicillin and penicillin G; specific examples of anti-infectivesinclude benzalkonium chloride and chlorhexidine; specific examples ofcoronary vasodilators include nitroglycerin and mioflazine; a specificexample of a hypnotic is etomidate; specific examples of carbonicanhydrase inhibitors include acetazolamide and chlorzolamide; specificexamples of antifungals include econazole, terconazole, fluconazole,voriconazole, and griseofulvin; a specific example of an antiprotozoalis metronidazole; specific examples of anthelmintic agents includethiabendazole and oxfendazole and morantel; specific examples ofantihistamines include astemizole, levocabastine, cetirizine,decarboethoxyloratadine, and cinnarizine; specific examples ofantipsychotics include ziprasidone, olanzepine, thiothixenehydrochloride, fluspirilene, risperidone and penfluridole; specificexamples of gastrointestinal agents include loperamide and cisapride;specific examples of serotonin antagonists include ketanserin andmianserin; a specific example of an anesthetic is lidocaine; a specificexample of a hypoglycemic agent is acetohexamide; a specific example ofan anti-emetic is dimenhydrinate; a specific example of an antibacterialis cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA;specific examples of anti-Alzheimer's Disease agents are THA anddonepezil; a specific example of an anti-ulcer agent/H2 antagonist isfamotidine; specific examples of sedative/hypnotic agents includechlordiazepoxide and triazolam; a specific example of a vasodilator isalprostadil; a specific example of a platelet inhibitor is prostacyclin;specific examples of ACE inhibitor/antihypertensive agents includeenalaprilic acid and lisinopril; specific examples of tetracyclineantibiotics include oxytetracycline and minocycline; specific examplesof macrolide antibiotics include erythromycin, clarithromycin, andspiramycin; a specific example of an azalide antibiotic is azithromycin;specific examples of glycogen phosphorylase inhibitors include[R—(R*S*)]-5-chloro-N-[2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide;and specific examples of cholesterol ester transfer protein (CETP)inhibitors include[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester,[2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester,[2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

The invention is not limited by any particular structure or group ofCETP inhibitors. Rather, the invention has general applicability to CETPinhibitors as a class, the class tending to be composed of compoundshaving low solubility. Compounds which may be the subject of theinvention may be found in a number of patents and publishedapplications, including DE 19741400 A1; DE 19741399 A1; WO 9914215 A1;WO 9914174; DE 19709125 A1; DE 19704244 A1; DE 19704243 A1; EP 818448A1; WO 9804528 A2; DE 19627431 A1; DE 19627430 A1; DE 19627419 A1; EP796846 A1; DE 19832159; DE 818197; DE 19741051; WO 9941237 A1; WO9914204 A1; WO 9835937 A1; JP 11049743; WO 200018721; WO 200018723; WO200018724; WO 200017164; WO 200017165; WO 200017166; EP 992496; and EP987251, all of which are hereby incorporated by reference in theirentireties for all purposes.

The invention is useful for CETP inhibitors that have sufficiently lowaqueous solubility, low bioavailability or slow rate of absorption suchthat it is desirable to increase their concentration in an aqueousenvironment of use. Therefore, anytime one finds it desirable to raisethe aqueous concentration of the CETP inhibitor in a use environment,the invention will find utility. The CETP inhibitor is “substantiallywater-insoluble” which means that the CETP inhibitor has a minimumaqueous solubility of less than about 0.01 mg/mL (or 10 μg/ml) at anyphysiologically relevant pH (e.g., pH 1-8) and at about 22° C. (Unlessotherwise specified, reference to aqueous solubility herein and in theclaims is determined at about 22° C.) Compositions of the presentinvention find greater utility as the solubility of the CETP inhibitorsdecreases, and thus are preferred for CETP inhibitors with solubilitiesless than about 2 μg/mL, and even more preferred for CETP inhibitorswith solubilities less than about 0.5 μg/mL. Many CETP inhibitors haveeven lower solubilities (some even less than 0.1 μg/mL), and requiredramatic concentration enhancement to be sufficiently bioavailable uponoral dosing for effective plasma concentrations to be reached atpractical doses.

In general, it may be said that the CETP inhibitor has a dose-to-aqueoussolubility ratio greater than about 100 mL, where the solubility (mg/mL)is the minimum value observed in any physiologically relevant aqueoussolution (e.g., those with pH values from 1 to 8) including USPsimulated gastric and intestinal buffers, and dose is in mg.Compositions of the present invention, as mentioned above, find greaterutility as the solubility of the CETP inhibitor decreases and the doseincreases. Thus, the compositions are preferred as thedose-to-solubility ratio increases, and thus are preferred fordose-to-solubility ratios greater than 1000 mL, and more preferred fordose-to-solubility ratios greater than about 5000 ml. Thedose-to-solubility ratio may be determined by dividing the dose (in mg)by the aqueous solubility (in mg/ml).

Oral delivery of many CETP inhibitors is particularly difficult becausetheir aqueous solubility is usually extremely low, typically being lessthan 2 μg/ml, often being less than 0.1 μg/ml. Such low solubilities area direct consequence of the particular structural characteristics ofspecies that bind to CETP and thus act as CETP inhibitors. This lowsolubility is primarily due to the hydrophobic nature of CETPinhibitors. Clog P, defined as the base 10 logarithm of the ratio of thedrug solubility in octanol to the drug solubility in water, is a widelyaccepted measure of hydrophobicity. In general, Clog P values for CETPinhibitors are greater than 4 and are often greater than 5 to 7. Thus,the hydrophobic and insoluble nature of CETP inhibitors as a class posea particular challenge for oral delivery. Achieving therapeutic druglevels in the blood by oral dosing of practical quantities of druggenerally requires a large enhancement in drug concentrations in thegastrointestinal fluid and a resulting large enhancement inbioavailability. Such enhancements in drug concentration ingastrointestsinal fluid typically need to be at least about 10-fold andoften at least about 50-fold or even at least about 200-fold to achievedesired blood levels. Surprisingly, the dispersions of the presentinvention have proven to have the required large enhancements in drugconcentration and bioavailability.

In contrast to conventional wisdom, the relative degree of enhancementin aqueous concentration and bioavailability generally improves for CETPinhibitors as solubility decreases and hydrophobocity increases. Infact, the inventors have recognized a subclass of these CETP inhibitorsthat are essentially aqueous insoluble, highly hydrophobic, and arecharacterized by a set of physical properties. This subclass exhibitsdramatic enhancements in aqueous concentration and bioavailability whenformulated using the compositions of the present invention.

The first property of this subclass of essentially insoluble,hydrophobic CETP inhibitors is extremely low aqueous solubility. Byextremely low aqueous solubility is meant that the minimum aqueoussolubility at physiologically relevant pH (pH of 1 to 8) is less thanabout 10 μg/ml and preferably less than about 1 μg/ml.

A second property is a very high does-to-solubility ratio. Extremely lowsolubility often leads to poor or slow absorption of the drug from thefluid of the gastrointestinal tract, when the drug is dosed orally in aconventional manner. For extremely low solubility drugs, poor absorptiongenerally becomes progressively more difficult as the dose (mass of druggiven orally) increases. Thus, a second property of this subclass ofessentially insoluble, hydrophobic CETP inhibitors is a very high dose(in mg) to solubility (in mg/ml) ratio (ml). By “very highdose-to-solubility ratio” is meant that the dose-to-solubility ratio hasa value of at least 1000 ml, and preferably at least 5,000 ml, and morepreferably at least 10,000 ml.

A third property of this subclass of essentially insoluble, hydrophobicCETP inhibitors is that they are extremely hydrophobic. By extremelyhydrophobic is meant that the Clog P value of the drug, has a value ofat least 4.0, preferably a value of at least 5.0, and more preferably avalue of at least 5.5.

A fourth property of this subclass of essentially insoluble CETPinhibitors is that they have a low melting point. Generally, drugs ofthis subclass will have a melting point of about 150° C. or less, andpreferably about 140° C. or less.

Primarily, as a consequence of some or all of these four properties,CETP inhibitors of this subclass typically have very low absolutebioavailabilities. Specifically, the absolute bioavailibility of drugsin this subclass when dosed orally in their undispersed state is lessthan about 10% and more often less than about 5%.

Turning now to the chemical structures of specific CETP inhibitors, oneclass of CETP inhibitors that finds utility with the present inventionconsists of oxy substituted4-carboxyamino-2-methyl-1,2,3,4-tetrahydroquinolines having the FormulaI

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;wherein R_(I), is hydrogen, Y_(I), W_(I)—X_(I), W_(I)—Y_(I);wherein W_(I) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;X_(I) is —O—Y_(I), —S—Y_(I), —N(H)—Y_(I) or —N—(Y_(I))₂;

wherein Y_(I) for each occurrence is independently Z_(I) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(I);

wherein Z_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxyl, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R_(I-3) is hydrogen or Q_(I);

wherein Q_(I) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I);

wherein V_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(I) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carbamoyl, mono-N- or di-N,N—(C₁-C₆)alkylcarbamoyl, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxyl,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines; R_(I-4) is Q_(I-1) orV_(I-1)

wherein Q_(I-1) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(I-1);

wherein V_(I-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(I-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(I-3) must contain V_(I) or R_(I-4) must containV_(I-1); and R_(I-5), R_(I-6), R_(I-7) and R_(I-8) are eachindependently hydrogen, hydroxy or oxy wherein said oxy is substitutedwith T_(I) or a partially saturated, fully saturated or fullyunsaturated one to twelve membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen and said carbon is optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(I);

wherein T_(I) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(I) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines.

Compounds of Formula I and their methods of manufacture are disclosed incommonly assigned U.S. Pat. No. 6,140,342, U.S. Pat. No. 6,362,198, andEuropean Patent publication 987251, all of which are incorporated hereinby reference in their entireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula I:

-   [2R,4S]4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-dinitro-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(2,6-dichloro-pyridin-4-ylmethyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid 2,2,2-trifluoro-ethylester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   [2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyryl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic    acid methyl ester;-   [2R,4S](3,5-bis-trifluoromethyl-benzyl)-(1-butyl-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic    acid methyl ester; and-   [2R,4S](3,5-bis-trifluoromethyl-benzyl)-[1-(2-ethyl-butyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic    acid methyl ester, hydrochloride.

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula II

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;wherein R_(II-1) is hydrogen, Y_(II), W_(II)—X_(II), W_(II)—Y_(II);wherein W_(II) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;X_(II) is —O—Y_(II), —S—Y_(II), —N(H)—Y_(II) or —N—(Y_(II))₂;

wherein Y_(II) for each occurrence is independently Z_(II) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(II);

Z_(II) is a partially saturated, fully saturated or fully unsaturatedthree to twelve membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl is also optionally substituted with from one to ninefluorines; R_(II-3) is hydrogen or Q_(II);

wherein Q_(II) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II);

wherein V_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(II) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are optionally substitutedwith from one to nine fluorines;

R_(II-4) is Q_(II-1) or V_(II-1)

wherein Q_(II-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(II-1);

wherein V_(II-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(II-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isoptionally substituted with from one to nine fluorines;

wherein either R_(II-3) must contain V_(II) or R_(II-4) must containV_(II-1); and

R_(II-5), R_(II-6), R_(II-7) and R_(II-8) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(II) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon may optionallybe replaced with one or two heteroatoms selected independently fromoxygen, sulfur and nitrogen wherein said carbon atoms are optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(II);

wherein T_(II) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(II) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

provided that at least one of substituents R_(II-5), R_(II-6), R_(II-7)and R_(II-8) is not hydrogen and is not linked to the quinoline moietythrough oxy.

Compounds of Formula II and their methods of manufacture are disclosedin commonly assigned U.S. Pat. No. 6,147,090, U.S. patent applicationSer. No. 09/671,400 filed Sep. 27, 2000, and PCT Publication No.WO00/17166, all of which are incorporated herein by reference in theirentireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula II:

-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-((3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2,6,7-trimethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-diethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-ethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester; and-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of annulated4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines, having theFormula III

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;wherein R_(III-1) is hydrogen, Y_(III), W_(III)—X_(III),W_(III)—Y_(III);wherein W_(III) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;X_(III) is —O—Y_(III), —S—Y_(III), —N(H)—Y_(III) or —N—(Y_(III))₂;

Y_(III) for each occurrence is independently Z_(III) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(III);

wherein Z_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(III) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl optionally substituted with from one to nine fluorines;

R_(III-3) is hydrogen or Q_(III);

wherein Q_(III) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III);

wherein V_(III) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(III) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino or said(C₁-C₆)alkyl or (C₂-C₆)alkenyl are optionally substituted with from oneto nine fluorines;

R_(III-4) is C_(III-1) or V_(III-1);

wherein Q_(III-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(III-1);

wherein V_(III-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(III-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituentoptionally having from one to nine fluorines;

wherein either R_(III-3) must contain V_(III) or R_(III-4) must containV_(III-1); and

R_(III-5) and R_(III-6), or R_(III-6) and R_(III-7), and/or R_(III-7)and R_(III-8) are taken together and form at least one four to eightmembered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(III-5) and R_(III-6), orR_(III-6) and R_(III-7), and/or R_(III-7) and R_(III-8) are optionallymono-, di- or tri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent optionally having from one to nine fluorines;

provided that the R_(III-5), R_(III-6), R_(III-7) and/or R_(III-8), asthe case may be, that do not form at least one ring are eachindependently hydrogen, halo, (C₁-C₆)alkoxy or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines.

Compounds of Formula III and their methods of manufacture are disclosedin commonly assigned U.S. Pat. No. 6,147,089, U.S. Pat. No. 6,310,075,and European Patent Application No. 99307240.4 filed Sep. 14, 1999, allof which are incorporated herein by reference in their entireties forall purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula II:

-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic    acid ethyl ester;-   [6R,8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-1H-2-thia-5-aza-cyclopenta[b]naphthalene-5-carboxylic    acid ethyl ester;-   [6R,8S]8-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-methyl-3,6,7,8-tetrahydro-2H-furo[2,3-g]quinoline-5-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[g]quinoline-1-carboxylic    acid propyl ester;-   [7R,9S]9-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-7-methyl-1,2,3,7,8,9-hexahydro-6-aza-cyclopenta[a]naphthalene-6-carboxylic    acid ethyl ester; and-   [6S,8R]6-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-methyl-1,2,3,6,7,8-hexahydro-9-aza-cyclopenta[a]naphthalene-9-carboxylic    acid ethyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of4-carboxyamino-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula IV

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;wherein R_(IV-1) is hydrogen, Y_(IV), W_(IV)—X_(IV) or W_(IV)—Y_(IV);wherein W_(IV) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;X_(IV) is —O—Y_(IV), —S—Y_(IV), —N(H)—Y_(IV) or —N—(Y_(IV))₂;

wherein Y_(IV) for each occurrence is independently Z_(IV) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(IV);

wherein Z_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(IV-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(IV-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(IV-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(IV-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl; with the proviso thatR_(IV-2) is not methyl; R_(IV-3) is hydrogen or Q_(IV);

wherein Q_(IV) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV);

wherein V_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(IV) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines; R_(IV-4) is Q_(IV-1) orV_(IV-1);

wherein Q_(IV-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(IV-1);

wherein V_(IV-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(IV-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R_(IV-3) must contain V_(IV) or R_(IV-4) must containV_(IV-1);

R_(IV-5), R_(IV-6), R_(IV-7) and R_(IV-6) are each independentlyhydrogen, a bond, nitro or halo wherein said bond is substituted withT_(IV) or a partially saturated, fully saturated or fully unsaturated(C₁-C₁₂) straight or branched carbon chain wherein carbon, mayoptionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T_(IV);

wherein T_(IV) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(IV) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

wherein R_(IV-5) and R_(IV-6), or R_(IV-6) and R_(IV-7), and/or R_(IV-7)and R_(IV-8) may also be taken together and can form at least one fourto eight membered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen;

wherein said ring or rings formed by R_(IV-5) and R_(IV-6), or R_(IV-6)and R_(IV-7), and/or R_(IV-7) and R_(IV-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R_(IV-2) is carboxyl or(C₁-C₄)alkylcarboxyl, then R_(IV-1) is not hydrogen.

Compounds of Formula IV and their methods of manufacture are disclosedin commonly assigned U.S. Pat. No. 6,197,786, U.S. application Ser. No.09/685,3000 filed Oct. 10, 2000, and PCT Publication No. WO 00/17164,all of which are incorporated herein by reference in their entiretiesfor all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula IV:

-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4R]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid 2-hydroxy-ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester; and-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-aminosubstituted-2-substituted-1,2,3,4,-tetrahydroquinolines, having theFormula V

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;

wherein R_(V-1) is Y_(V), W_(V)—X_(V) or W_(V)—Y_(V);

wherein W_(V) is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X_(V) is —O—Y_(V), —S—Y_(V), —N(H)—Y_(V) or —N—(Y_(V))₂;

wherein Y_(V) for each occurrence is independently Z_(V) or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z_(V);

wherein Z_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said Z_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R_(V-2) is a partially saturated, fully saturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one or two heteroatoms selected independently from oxygen, sulfurand nitrogen wherein said carbon atoms are optionally mono-, di- ortri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R_(V-2) is a partially saturated, fully saturated or fullyunsaturated three to seven membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen,wherein said R_(V-2) ring is optionally attached through (C₁-C₄)alkyl;

wherein said R_(V-2) ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

R_(V-3) is hydrogen or Q_(V);

wherein Q_(V) is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V_(V);

wherein V_(V) is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N—(C₁-C₆)alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R_(V-4) is cyano, formyl, W_(V-1)Q_(V-1), W_(V-1)V_(V-1),(C₁-C₄)alkyleneV_(V-1) or V_(V-2);

wherein W_(V-1) is carbonyl, thiocarbonyl, SO or SO₂,

wherein Q_(V-1) a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons may optionally be replaced with one heteroatomselected from oxygen, sulfur and nitrogen and said carbon is optionallymono-, di- or tri-substituted independently with halo, said carbon isoptionally mono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V_(V-1);

wherein V_(V-1) is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said V_(V-1) substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,hydroxy, oxo, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N—(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein V_(V-2) is a partially saturated, fully saturated or fullyunsaturated five to seven membered ring containing one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V_(V-2) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₂)alkyl, (C₁-C₂)alkoxy,hydroxy, or oxo wherein said (C₁-C₂)alkyl optionally has from one tofive fluorines; and

wherein R_(V-4) does not include oxycarbonyl linked directly to the C⁴nitrogen;

wherein either R_(V-3) must contain V_(V) or R_(V-4) must containV_(V-1);

R_(V-5), R_(V-6), R_(V-7) and R_(V-4) are independently hydrogen, abond, nitro or halo wherein said bond is substituted with T_(V) or apartially saturated, fully saturated or fully unsaturated (C₁-C₁₂)straight or branched carbon chain wherein carbon may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen, wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with hydroxy, said carbon is optionallymono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with T_(V);

wherein T_(V) is a partially saturated, fully saturated or fullyunsaturated three to twelve membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, ora bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen;

wherein said T_(V) substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylaminowherein said (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines;

wherein R_(V-5) and R_(V-6), or R_(V-6) and R_(V-7), and/or R_(V-7) andR_(V-8) may also be taken together and can form at least one ring thatis a partially saturated or fully unsaturated four to eight memberedring optionally having one to three heteroatoms independently selectedfrom nitrogen, sulfur and oxygen;

wherein said rings formed by R_(V-5) and R_(V-6), or R_(V-6) andR_(V-7), and/or R_(V-7) and R_(V-8) are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N—(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent also optionally has from one to nine fluorines.

Compounds of Formula V and their methods of manufacture are disclosed incommonly assigned U.S. Pat. No. 6,140,343, U.S. patent application Ser.No. 09/671,221 filed Sep. 27, 2000, and PCT Publication No. WO 00/17165,all of which are incorporated herein by reference in their entiretiesfor all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula V:

-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[1-(3,5-bis-trifluoromethyl-benzyl)-ureido]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid propyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester;-   [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-formyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester; and-   [2R,4S]4-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic    acid isopropyl ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of cycloalkano-pyridines having the Formula VI

and pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds;in which

A_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —BNR_(VI-3)R_(VI-4), wherein

R_(VI-3) and R_(VI-4) are identical or different and denote a hydrogen,phenyl or a straight-chain or branched alkyl containing up to 6 carbonatoms,

D_(VI) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formulaR_(VI-5)-L_(VI)-,

or R_(VI-9)-T_(VI)-V_(VI)—X_(VI), wherein

R_(VI-5), R_(VI-6) and R_(VI-9) denote, independently from one another,a cycloalkyl containing 3 to 6 carbon atoms, or an aryl containing 6 to10 carbon atom or a 5- to 7-membered, optionally benzo-condensed,saturated or unsaturated, mono-, bi- or tricyclic heterocycle containingup to 4 heteroatoms from the series of S, N and/or O, wherein the ringsare optionally substituted, in the case of the nitrogen-containing ringsalso via the N function, with up to five identical or differentsubstituents in the form of a halogen, trifluoromethyl, nitro, hydroxyl,cyano, carboxyl, trifluoromethoxy, a straight-chain or branched acyl,alkyl, alkylthio, alkylalkoxy, alkoxy or alkoxycarbonyl containing up to6 carbon atoms each, an aryl or trifluoromethyl-substituted arylcontaining 6 to 10 carbon atoms each, or an optionally benzo-condensed,aromatic 5- to 7-membered heterocycle containing up to 3 heteroatomsfrom the series of S, N and/or O, and/or in the form of a groupaccording to the formula BOR_(VI-10), —SR_(VI-11), —SO₂R_(VI-12) orBNR_(VI-13)R_(VI-14), wherein

R_(VI-10), R_(VI-11) and R_(VI-12) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(VI-13) and R_(VI-14) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-5) and/or R_(VI-6) denote a radical according to the formula

R_(VI-7) denotes a hydrogen or halogen, and

R_(VI-8) denotes a hydrogen, halogen, azido, trifluoromethyl, hydroxyl,trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula—NR_(VI-15)R_(VI-16),wherein

R_(VI-15) and R_(VI-16) are identical or different and have the meaningof R_(VI-3) and R_(VI-4) given above, or

R_(VI-7) and R_(VI-8) together form a radical according to the formula═O or ═NR_(VI-17), wherein

R_(VI-17) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each,

L_(VI) denotes a straight-chain or branched alkylene or alkenylene chaincontaining up to 8 carbon atoms each, which are optionally substitutedwith up to two hydroxyl groups,

T_(VI) and X_(VI) are identical or different and denote a straight-chainor branched alkylene chain containing up to 8 carbon atoms, or

T_(VI) or X_(VI) denotes a bond,

V_(VI) denotes an oxygen or sulfur atom or an BNR_(VI-18) group, wherein

R_(VI-18) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl,

E_(VI) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl,

R_(VI-1) and R_(VI-2) together form a straight-chain or branchedalkylene chain containing up to 7 carbon atoms, which must besubstituted with a carbonyl group and/or a radical according to theformula

wherein

a and b are identical or different and denote a number equaling 1, 2 or3,

R_(VI-19) denotes a hydrogen atom, a cycloalkyl containing 3 to 7 carbonatoms, a straight-chain or branched silylalkyl containing up to 8 carbonatoms, or a straight-chain or branched alkyl containing up to 8 carbonatoms, which is optionally substituted with a hydroxyl, a straight-chainor a branched alkoxy containing up to 6 carbon atoms or a phenyl, whichmay in turn be substituted with a halogen, nitro, trifluoromethyl,trifluoromethoxy or phenyl or tetrazole-substituted phenyl, and an alkylthat is optionally substituted with a group according to the formulaBOR_(VI-22), wherein

R_(VI-22) denotes a straight-chain or branched acyl containing up to 4carbon atoms or benzyl, or

R_(VI-19) denotes a straight-chain or branched acyl containing up to 20carbon atoms or benzoyl, which is optionally substituted with a halogen,trifluoromethyl, nitro or trifluoromethoxy, or a straight-chain orbranched fluoroacyl containing up to 8 carbon atoms,

R_(VI-20) and R_(VI-21) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms, or

R_(VI-20) and R_(VI-21) together form a 3- to 6-membered carbocyclicring, and a the carbocyclic rings formed are optionally substituted,optionally also geminally, with up to six identical or differentsubstituents in the form of trifluoromethyl, hydroxyl, nitrile, halogen,carboxyl, nitro, azido, cyano, cycloalkyl or cycloalkyloxy containing 3to 7 carbon atoms each, a straight-chain or branched alkoxycarbonyl,alkoxy or alkylthio containing up to 6 carbon atoms each, or astraight-chain or branched alkyl containing up to 6 carbon atoms, whichis in turn substituted with up to two identical or differentsubstituents in the form of a hydroxyl, benzyloxy, trifluoromethyl,benzoyl, a straight-chain or branched alkoxy, oxyacyl or carboxylcontaining up to 4 carbon atoms each and/or a phenyl, which may in turnbe substituted with a halogen, trifluoromethyl or trifluoromethoxy,and/or the carbocyclic rings formed are optionally substituted, alsogeminally, with up to five identical or different substituents in theform of a phenyl, benzoyl, thiophenyl or sulfonylbenzyl, which in turnare optionally substituted with a halogen, trifluoromethyl,trifluoromethoxy or nitro, and/or optionally in the form of a radicalaccording to the formula

wherein

c is a number equaling 1, 2, 3 or 4,

d is a number equaling 0 or 1,

R_(VI-23) and R_(VI-24) are identical or different and denote ahydrogen, cycloalkyl containing 3 to 6 carbon atoms, a straight-chain orbranched alkyl containing up to 6 carbon atoms, benzyl or phenyl, whichis optionally substituted with up to two identical or differentsubstituents in the form of halogen, trifluoromethyl, cyano, phenyl ornitro, and/or the carbocyclic rings formed are optionally substitutedwith a spiro-linked radical according to the formula

wherein

W_(VI) denotes either an oxygen atom or a sulfur atom,

Y_(VI) and Y=_(VI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number equaling 1, 2, 3, 4, 5, 6 or 7,

f is a number equaling 1 or 2,

R_(VI-25), R_(VI-26), R_(VI-27), R_(VI-28), R_(VI-29), R_(VI-30) andR_(VI-31) are identical or different and denote a hydrogen,trifluoromethyl, phenyl, halogen or a straight-chain or branched alkylor alkoxy containing up to 6 carbon atoms each, or

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together denotea straight-chain or branched alkyl chain containing up to 6 carbon atomsor

R_(VI-25) and R_(VI-26) or R_(VI-27) and R_(VI-28) each together form aradical according to the formula

wherein

W_(VI) has the meaning given above,

g is a number equaling 1, 2, 3, 4, 5, 6 or 7,

R_(VI-32) and R_(VI-33) together form a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group according to theformula SO, SO₂ or BNR_(VI-34), wherein

R_(VI-34) denotes a hydrogen atom, a phenyl, benzyl, or a straight-chainor branched alkyl containing up to 4 carbon atoms, and salts and Noxides thereof, with the exception of 5(6H)-quinolones,3-benzoyl-7,8-dihydro-2,7,7-trimethyl-4-phenyl.

Compounds of Formula VI and their methods of manufacture are disclosedin European Patent Application No. EP 818448 A1, U.S. Pat. No. 6,207,671and U.S. Pat. No. 6,069,148, all of which are incorporated herein byreference in their entireties for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from one ofthe following compounds of Formula VI:

-   2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one;-   2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-7,8-dihydro-6H-quinolin-5-one;-   [2-cyclopentyl-4-(4-fluorophenyl)-5-hydroxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;-   [5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone;-   [5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol;-   5-(t-butyldimethylsilanyloxy)-2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline;    and-   2-cyclopentyl-4-(4-fluorophenyl)-3-[fluoro-(4-trifluoromethylphenyl)-methyl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted-pyridines having the Formula VII

or a pharmaceutically acceptable salt or tautomer thereof,

wherein R_(VII-2) and R_(VII-6) are independently selected from thegroup consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl,fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl,aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided thatat least one of R_(VII-2) and R_(VII-6) is fluorinated alkyl,chlorofluorinated alkyl or alkoxyalkyl;

R_(VII-3) is selected from the group consisting of hydroxy, amido,arylcarbonyl, heteroarylcarbonyl, hydroxymethyl

—CHO,

—CO₂R_(VII-7), wherein R_(VII-7) is selected from the group consistingof hydrogen, alkyl and cyanoalkyl; and

wherein R_(VII-15a) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy and heterocyclyloxy, and

R_(VII-16a) is selected from the group consisting of alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, andheterocyclyl, arylalkoxy, trialkylsilyloxy;

R_(VII-4) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl,cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl,hetereoarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy,aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy,alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy,alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio,alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio,cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl,alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl,heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl,alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl,heterocyclythioalkenyl, alkylamino, alkenylamino, alkynylamino,arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino,diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino,arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,—CO(O)N(R_(VII-8a)R_(VII-8b)), wherein R_(VII-8a) and R_(VII-8b) areindependently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl, —SO₂R_(VII-9), whereinR_(VII-9) is selected from the group consisting of hydroxy, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,—OP(O)(OR_(VII-10a)) (OR_(VII-10b)), wherein R_(VII-10a) and R_(VII-10b)are independently selected from the group consisting of hydrogen,hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and—OP(S)(OR_(VII-11a))(OR_(VII-11b)), wherein R_(VII-11a) and R_(VII-11b)are independently selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

R_(VII-5) is selected from the group consisting of hydrogen, hydroxy,halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl,haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy,alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl,arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl,heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl,aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl,arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl,alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl,arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl,alkoxyalkyl, alkenoxyalkyl, alkynoxylalkyl, aryloxyalkyl,heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl,alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl,heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R_(VII-14), whereinR_(VII-14) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-15b) is selected from the group consisting of hydroxy,hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy,heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(VII-16b) is selected form the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, andtrialkylsilyloxy;

wherein R_(VII-17) and R_(VII-18) are independently selected from thegroup consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl and heterocyclyl;

wherein R_(VII-19) is selected from the group consisting of alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,—SR_(VII-20), —OR_(VII-21), and BR_(VII-22)CO₂R_(VII-23), wherein

R_(VII-20) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl,aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl,alkylheteroarylamino, arylheteroarylamino,

R_(VII-21) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl,

R_(VII-22) is selected from the group consisting of alkylene or arylene,and

R_(VII-23) is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R_(VI-24) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,aralkyl, aralkenyl, and aralkynyl;

wherein R_(VII-25) is heterocyclylidenyl;

wherein R_(VII-26) and R_(VII-27) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-28) and R_(VII-29) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VI-30) and R_(VII-31) are independently alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R_(VII-32) and R_(VII-33) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-36) is selected from the group consisting of alkyl,alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R_(VII-37) and R_(VII-38) are independently selected from thegroup consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, and heterocyclyl;

wherein R_(VII-39) is selected from the group consisting of hydrogen,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy,alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio andheterocyclylthio, and

R_(VII-40) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy,heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio,heteroarylthio and heterocyclylthio;—N═R_(VI-41),

wherein R_(VI-41) is heterocyclylidenyl;

wherein R_(VII-42) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R_(VII-43) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl,cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl,haloheteroaryl, and haloheterocyclyl;

wherein R_(VII-44) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;—N═S═O;—N═C═S;—N═C═O;—N₃;—SR_(VII-45)

wherein R_(VII-45) is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl,heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl,heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl,cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl,alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl,heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl,alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl,heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl,aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl,aminocarbonylheteroaryl, and aminocarbonylheterocyclyl,

—SR_(VII-46), and —CH₂R_(VII-47),

wherein R_(VII-46) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R_(VII-47) is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R_(VII-48) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,and

R_(VII-49) is selected from the group consisting of alkoxy, alkenoxy,alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R_(VII-50) is selected from the group consisting of hydrogen,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl,alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R_(VII-51) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl,haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;and

wherein R_(VII-53) is selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

provided that when R_(VII-5) is selected from the group consisting ofheterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical ofthe corresponding heterocyclylalkyl or heterocyclylalkenyl is other thanδ-lactone; and

provided that when R_(VII-4) is aryl, heteroaryl or heterocyclyl, andone of R_(VII-2) and R_(VII-6) is trifluoromethyl, then the other ofR_(VII-2) and R_(VI-6) is difluoromethyl.

Compounds of Formula VII and their methods of manufacture are disclosedin PCT Publication No. WO 9941237-A1, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor of Formula VII is dimethyl5,5-dithiobis[2-difluoromethyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine-carboxylate].

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted biphenyls having the Formula VIII

or a pharmaceutically acceptable salt, enantiomers, or stereoisomersthereof, in which

A_(VIII) stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula —NR_(VIII-1)R_(VIII-2), wherein

R_(VIII-1) and R_(VIII-2) are identical or different and denotehydrogen, phenyl, or straight-chain or branched alkyl with up to 6carbon atoms,

D_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

E_(VIII) and L_(VIII) are either identical or different and stand forstraight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by cycloalkyl with 3 to 8 carbon atoms, or standsfor cycloalkyl with 3 to 8 carbon atoms, or

E_(VIII) has the above-mentioned meaning and

L_(VIII) in this case stands for aryl with 6 to 10 carbon atoms, whichis optionally substituted up to 3 times in an identical manner ordifferently by halogen, hydroxy, trifluoromethyl, trifluoromethoxy, orby straight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-3)R_(VIII-4), wherein

R_(VIII-3) and R_(VIII-4) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

E_(VIII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, or stands for aryl with 6 to 10 carbon atoms, which is optionallysubstituted up to 3 times in an identical manner or differently byhalogen, hydroxy, trifluoromethyl, trifluoromethoxy, or bystraight-chain or branched alkyl, acyl, or alkoxy with up to 7 carbonatoms each, or by a group of the formula—NR_(VIII-5)R_(VIII-6), wherein

R_(VIII-5) and R_(VIII-6) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), and

L_(VIII) in this case stands for straight-chain or branched alkoxy withup to 8 carbon atoms or for cycloalkyloxy with 3 to 8 carbon atoms,

T_(VIII) stands for a radical of the formula

R_(VIII-7) and R_(VIII-8) are identical or different and denotecycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or denote a 5- to 7-member aromatic, optionally benzo-condensed,heterocyclic compound with up to 3 heteroatoms from the series S, Nand/or O, which are optionally substituted up to 3 times in an identicalmanner or differently by trifluoromethyl, trifluoromethoxy, halogen,hydroxy, carboxyl, by straight-chain or branched alkyl, acyl, alkoxy, oralkoxycarbonyl with up to 6 carbon atoms each, or by phenyl, phenoxy, orthiophenyl, which can in turn be substituted by halogen,trifluoromethyl, or trifluoromethoxy, and/or the rings are substitutedby a group of the formula—NR_(VIII-11)R_(VIII-12), wherein

R_(VIII-11) and R_(VIII-12) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2),

X_(VIII) denotes a straight or branched alkyl chain or alkenyl chainwith 2 to 10 carbon atoms each, which are optionally substituted up to 2times by hydroxy,

R_(VIII-9) denotes hydrogen, and

R_(VIII-10) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,mercapto, trifluoromethoxy, straight-chain or branched alkoxy with up to5 carbon atoms, or a radical of the formula—NR_(VIII-13)R_(VIII-14), wherein

R_(VIII-13) and R_(VIII-14) are identical or different and have themeaning given above for R_(VIII-1) and R_(VIII-2), or

R_(VIII-9) and R_(VIII-10) form a carbonyl group together with thecarbon atom.

Compounds of Formula VIII are disclosed in PCT Publication No. WO9804528, which is incorporated herein by reference in its entirety forall purposes.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted 1,2,4-triazoles having the Formula IX

or a pharmaceutically acceptable salt or tautomer thereof;

wherein R_(IX-1) is selected from higher alkyl, higher alkenyl, higheralkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl, alkylthioalkyl,arylthioalkyl, and cycloalkylalkyl;

wherein R_(IX-2) is selected from aryl, heteroaryl, cycloalkyl, andcycloalkenyl, wherein R_(IX-2) is optionally substituted at asubstitutable position with one or more radicals independently selectedfrom alkyl, haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxy,halo, aryloxy, aralkyloxy, aryl, aralkyl, aminosulfonyl, amino,monoalkylamino and dialkylamino; and

wherein R_(IX-3) is selected from hydrido, —SH and halo; providedR_(IX-2) cannot be phenyl or 4-methylphenyl when R_(IX-1) is higheralkyl and when R_(IX-3) is BSH.

Compounds of Formula IX and their methods of manufacture are disclosedin PCT Publication No. WO 9914204, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula IX:

-   2,4-dihydro-4-(3-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-fluorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-cyclohexyl-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-pyridyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-ethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2,6-dimethylphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-phenoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(1,3-benzodioxol-5-yl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(2-chlorophenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-methoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(3-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(3-fluorophenyl)-3H-1,2,4-triazole-3-thione;-   4-(3-chloro-4-methylphenyl)-2.4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(4-benzyloxyphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-tridecyl-4-(4-trifluoromethylphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(1-naphthyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(4-methylthiophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3,4-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2,5-dimethoxyphenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(2-methoxy-5-chlorophenyl)-5-tridecyl-3H-1,2,4-triazole-3-thione;-   4-(4-aminosulfonylphenyl)-2,4-dihydro-5-tridecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-5-dodecyl-4-(3-methoxyphenyl)-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methoxyphenyl)-5-tetradecyl-3H-1,2,4-triazole-3-thione;-   2,4-dihydro-4-(3-methoxyphenyl)-5-undecyl-3H-1,2,4-triazole-3-thione;    and-   2,4-dihydro-(4-methoxyphenyl)-5-pentadecyl-3H-1,2,4-triazole-3-thione.

Another class of CETP inhibitors that finds utility with the presentinvention consists of hetero-tetrahydroquinolines having the Formula X

and pharmaceutically acceptable salts, enantiomers, or stereoisomers orN-oxides of said compounds;in which

A_(X) represents cycloalkyl with 3 to 8 carbon atoms or a 5 to7-membered, saturated, partially saturated or unsaturated, optionallybenzo-condensed heterocyclic ring containing up to 3 heteroatoms fromthe series comprising S, N and/or O, that in case of a saturatedheterocyclic ring is bonded to a nitrogen function, optionally bridgedover it, and in which the aromatic systems mentioned above areoptionally substituted up to 5-times in an identical or differentsubstituents in the form of halogen, nitro, hydroxy, trifluoromethyl,trifluoromethoxy or by a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy each having up to 7 carbon atoms or by a group ofthe formula BNR_(X-3)R_(X-4),

in which

R_(X-3) and R_(X-4) are identical or different and denote hydrogen,phenyl or straight-chain or branched alkyl having up to 6 carbon atoms,or

A_(X) represents a radical of the formula

D_(X) represents an aryl having 6 to 10 carbon atoms, that is optionallysubstituted by phenyl, nitro, halogen, trifluormethyl ortrifluormethoxy, or it represents a radical of the formula

in which

R_(X-5), R_(X-6) and R_(X-9) independently of one another denotecycloalkyl having 3 to 6 carbon atoms, or an aryl having 6 to 10 carbonatoms or a 5- to 7-membered aromatic, optionally benzo-condensedsaturated or unsaturated, mono-, bi-, or tricyclic heterocyclic ringfrom the series consisting of S, N and/or O, in which the rings aresubstituted, optionally, in case of the nitrogen containing aromaticrings via the N function, with up to 5 identical or differentsubstituents in the form of halogen, trifluoromethyl, nitro, hydroxy,cyano, carbonyl, trifluoromethoxy, straight straight-chain or branchedacyl, alkyl, alkylthio, alkylalkoxy, alkoxy, or alkoxycarbonyl eachhaving up to 6 carbon atoms, by aryl or trifluoromethyl-substituted aryleach having 6 to 10 carbon atoms or by an, optionally benzo-condensed,aromatic 5- to 7-membered heterocyclic ring having up to 3 heteroatomsfrom the series consisting of S, N, and/or O, and/or substituted by agroup of the formula BOR_(X-10), —SR_(X-11), SO₂R_(X-12) orBNR_(X-13)R_(X-14),

in which

R_(X-10), R_(X-11) and R_(X-12) independently from each other denotearyl having 6 to 10 carbon atoms, which is in turn substituted with upto 2 identical or different substituents in the form of phenyl, halogenor a straight-chain or branched alkyl having up to 6 carbon atoms,

R_(X-13) and R_(X-14) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above, or

R_(X-5) and/or R_(X-6) denote a radical of the formula

R_(X-7) denotes hydrogen or halogen, and

R_(X-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl having upto 6 carbon atoms or a radical of the formulaBNR_(X-15)R_(X-16),in which

R_(X-15) and R_(X-16) are identical or different and have the meaning ofR_(X-3) and R_(X-4) indicated above, or

R_(X-7) and R_(X-8) together form a radical of the formula ═O or═NR_(X-17),

in which

R_(X-17) denotes hydrogen or straight chain or branched alkyl, alkoxy oracyl having up to 6 carbon atoms,

L_(X) denotes a straight chain or branched alkylene or alkenylene chainhaving up to 8 carbon atoms, that are optionally substituted with up to2 hydroxy groups,

T_(X) and X_(X) are identical or different and denote a straight chainor branched alkylene chain with up to 8 carbon atoms or

T_(X) or X_(X) denotes a bond,

V_(X) represents an oxygen or sulfur atom or an BNR_(X-18)— group, inwhich

R_(X-18) denotes hydrogen or straight chain or branched alkyl with up to6 carbon atoms or phenyl,

E_(X) represents cycloalkyl with 3 to 8 carbon atoms, or straight chainor branched alkyl with up to 8 carbon atoms, that is optionallysubstituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy, orrepresents a phenyl, that is optionally substituted by halogen ortrifluoromethyl,

R_(X-1) and R_(X-2) together form a straight-chain or branched alkylenechain with up to 7 carbon atoms, that must be substituted by carbonylgroup and/or by a radical with the formula

in which a and b are identical or different and denote a number equaling1, 2, or 3,

R_(X-19) denotes hydrogen, cycloalkyl with 3 up to 7 carbon atoms,straight chain or branched silylalkyl with up to 8 carbon atoms orstraight chain or branched alkyl with up to 8 carbon atoms, that areoptionally substituted by hydroxyl, straight chain or branched alkoxywith up to 6 carbon atoms or by phenyl, which in turn might besubstituted by halogen, nitro, trifluormethyl, trifluoromethoxy or byphenyl or by tetrazole-substituted phenyl, and alkyl, optionally besubstituted by a group with the formula BOR_(X-22),

in which

R_(X-22) denotes a straight chain or branched acyl with up to 4 carbonatoms or benzyl, or

R_(X-19) denotes straight chain or branched acyl with up to 20 carbonatoms or benzoyl, that is optionally substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or it denotes straight chainor branched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(X-20) and R_(X-21) are identical or different and denote hydrogen,phenyl or straight chain or branched alkyl with up to 6 carbon atoms,

or

R_(X-20) and R_(X-21) together form a 3- to 6-membered carbocyclic ring,and the carbocyclic rings formed are optionally substituted, optionallyalso geminally, with up to six identical or different substituents inthe form of triflouromethyl, hydroxy, nitrile, halogen, carboxyl, nitro,azido, cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each,by straight chain or branched alkoxycarbonyl, alkoxy or alkylthio withup to 6 carbon atoms each or by straight chain or branched alkyl with upto 6 carbon atoms, which in turn is substituted with up to 2 identicallyor differently by hydroxyl, benzyloxy, trifluoromethyl, benzoyl,straight chain or branched alkoxy, oxyacyl or carbonyl with up to 4carbon atoms each and/or phenyl, which may in turn be substituted with ahalogen, trifuoromethyl or trifluoromethoxy, and/or the formedcarbocyclic rings are optionally substituted, also geminally, with up to5 identical or different substituents in the form of phenyl, benzoyl,thiophenyl or sulfonylbenzyl, which in turn are optionally substitutedby halogen, trifluoromethyl, trifluoromethoxy or nitro, and/oroptionally are substituted by a radical with the formula

in which

c denotes a number equaling 1, 2, 3, or 4,

d denotes a number equaling 0 or 1,

R_(X-23) and R_(X-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, that is optionallysubstituted with up to 2 identically or differently by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the formed carbocyclicrings are substituted optionally by a spiro-linked radical with theformula

in which

W_(X) denotes either an oxygen or a sulfur atom

Y_(X) and Y_(X) together form a 2 to 6 membered straight chain orbranched alkylene chain,

e denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

f denotes a number equaling 1 or 2,

R_(X-25), R_(X-26), R_(X-27), R_(X-28), R_(X-29), R_(X-30) and R_(X-31)are identical or different and denote hydrogen, trifluoromethyl, phenyl,halogen or straight chain or branched alkyl or alkoxy with up to 6carbon atoms each,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) respectively formtogether a straight chain or branched alkyl chain with up to 6 carbonatoms,

or

R_(X-25) and R_(X-26) or R_(X-27) and R_(X-28) each together form aradical with the formula

in which

W_(X) has the meaning given above,

g denotes a number equaling 1, 2, 3, 4, 5, 6, or 7,

R_(X-32) and R_(X-33) form together a 3- to 7-membered heterocycle,which contains an oxygen or sulfur atom or a group with the formula SO,SO₂ or—NR_(X-34),in which

R_(X-34) denotes hydrogen, phenyl, benzyl or straight or branched alkylwith up to 4 carbon atoms.

Compounds of Formula X and their methods of manufacture are disclosed inPCT Publication No. WO 9914215, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula X:

-   2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(4-trifluoromethylbenxoyl)-5,6,7,8-tetrahydroquinoline;-   2-cyclopentyl-3-[fluoro-(4-trifluoromethylphenyl)methyl]-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-5,6,7,8-tetrahydroquinoline;    and-   2-cyclopentyl-5-hydroxy-7,7-dimethyl-4-(3-thienyl)-3-(trifluoromethylbenxyl)-5,6,7,8-tetrahydroquinoline.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted tetrahydro naphthalines and analogouscompound having the Formula XI

and stereoisomers, stereoisomer mixtures, and salts thereof, in which

A_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands foraryl with 6 to 10 carbon atoms, or stands for a 5- to 7-membered,saturated, partially unsaturated or unsaturated, possiblybenzocondensated, heterocycle with up to 4 heteroatoms from the seriesS, N and/or O, where aryl and the heterocyclic ring systems mentionedabove are substituted up to 5-fold, identical or different, by cyano,halogen, nitro, carboxyl, hydroxy, trifluoromethyl, trifluoro-methoxy,or by straight-chain or branched alkyl, acyl, hydroxyalkyl, alkylthio,alkoxycarbonyl, oxyalkoxycarbonyl or alkoxy each with up to 7 carbonatoms, or by a group of the formula—NR_(XI-3)R_(XI-4),in which

R_(XI-3) and R_(XI-4) are identical or different and denote hydrogen,phenyl, or straight-chain or branched alkyl with up to 6 carbon atoms

D_(XI) stands for a radical of the formula

in which

R_(XI-5), R_(XI-6) and R_(XI-9), independent of each other, denotecycloalkyl with 3 to 6 carbon atoms, or denote aryl with 6 to 10 carbonatoms, or denote a 5- to 7-membered, possibly benzocondensated,saturated or unsaturated, mono-, bi- or tricyclic heterocycle with up to4 heteroatoms of the series S, N and/or O, where the cycles are possiblysubstituted C in the case of the nitrogen-containing rings also via theN-function C up to 5-fold, identical or different, by halogen,trifluoromethyl. nitro, hydroxy, cyano, carboxyl, trifluoromethoxy,straight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl with up to 6 carbon atoms each. by aryl ortrifluoromethyl substituted aryl with 6 to 10 carbon atoms each, or by apossibly benzocondensated aromatic 5- to 7-membered heterocycle with upto 3 heteroatoms of the series S, N and/or O, and/or are substituted bya group of the formula—OR_(XI-10),—SR_(XI-11),—SO₂R_(XI-12) or—NR_(XI-13)R_(XI-14),in which

R_(XI-10), R_(XI-11) and R_(XI-12), independent of each other, denotearyl with 6 to 10 carbon atoms, which itself is substituted up to2-fold, identical or different, by phenyl, halogen. or by straight-chainor branched alkyl with up to 6 carbon atoms,

R_(XI-13) and R_(XI-14) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4),

or

R_(XI-5) and/or R_(XI-6) denote a radical of the formula

R_(XI-7) denotes hydrogen, halogen or methyl, and

R_(XI-8) denotes hydrogen, halogen, azido, trifluoromethyl, hydroxy,trifluoromethoxy, straight-chain or branched alkoxy or alkyl with up to6 carbon atoms each, or a radical of the formula —NR_(XI-15)R_(XI-16),

in which

R_(XI-15) and R_(XI-16) are identical or different and have the meaninggiven above for R_(XI-3) and R_(XI-4), or

R_(XI-7) and R_(XI-8) together form a radical of the formula ═O or═NR_(XI-17), in which

R_(XI-17) denotes hydrogen or straight-chain or branched alkyl, alkoxyor acyl with up to 6 carbon atoms each,

L_(XI) denotes a straight-chain or branched alkylene- or alkenylenechain with up to 8 carbon atoms each, which is possibly substituted upto 2-fold by hydroxy,

T_(XI) and X_(XI) are identical or different and denote a straight-chainor branched alkylene chain with up to 8 carbon atoms,

or

T_(XI) and X_(XI) denotes a bond,

V_(XI) stands for an oxygen- or sulfur atom or for an —NR_(XI-18) group,

in which

R_(XI-18) denotes hydrogen or straight-chain or branched alkyl with upto 6 carbon atoms, or phenyl,

E_(XI) stands for cycloalkyl with 3 to 8 carbon atoms, or stands forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms or hydroxy,or stands for phenyl, which is possibly substituted by halogen ortrifluoromethyl,

R_(XI-1) and R_(XI-2) together form a straight-chain or branchedalkylene chain with up to 7 carbon atoms, which must be substituted by acarbonyl group and/or by a radical of the formula

in which

a and b are identical or different and denote a number 1, 2 or 3

R_(XI-19) denotes hydrogen, cycloalkyl with 3 to 7 carbon atoms,straight-chain or branched silylalkyl with up to 8 carbon atoms, orstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or by phenyl, which itself can be substituted byhalogen, nitro, trifluoromethyl, trifluoromethoxy or by phenylsubstituted by phenyl or tetrazol, and alkyl is possibly substituted bya group of the formula —OR_(XI-22),

in which

R_(XI-22) denotes straight-chain or branched acyl with up to 4 carbonatoms, or benzyl, or

R_(XI-19) denotes straight-chain or branched acyl with up to 20 carbonatoms or benzoyl, which is possibly substituted by halogen,trifluoromethyl, nitro or trifluoromethoxy, or denotes straight-chain orbranched fluoroacyl with up to 8 carbon atoms and 9 fluorine atoms,

R_(XI-20) and R_(XI-21) are identical or different, denoting hydrogen,phenyl or straight-chain or branched alkyl with up to 6 carbon atoms,

or

R_(XI-20) and R_(XI-21) together form a 3- to 6-membered carbocycle,and, possibly also geminally, the alkylene chain formed by R_(XI-1) andR_(XI-2), is possibly substituted up to 6-fold, identical or different,by trifluoromethyl, hydroxy, nitrile, halogen, carboxyl, nitro, azido,cyano, cycloalkyl or cycloalkyloxy with 3 to 7 carbon atoms each, bystraight-chain or branched alkoxycarbonyl, alkoxy or alkoxythio with upto 6 carbon atoms each, or by straight-chain or branched alkyl with upto 6 carbon atoms, which itself is substituted up to 2-fold,

identical or different. by hydroxyl, benzyloxy, trifluoromethyl,benzoyl, straight-chain or branched alkoxy, oxyacyl or carboxyl with upto 4 carbon atoms each, and/or phenyl—which itself can be substituted byhalogen, trifluoromethyl or trifluoromethoxy, and/or the alkylene chainformed by R_(XI-1), and R_(XI-2) is substituted, also geminally,possibly up to 5-fold, identical or different, by phenyl, benzoyl,thiophenyl or sulfobenzyl—which themselves are possibly substituted byhalogen, trifluoromethyl, trifluoromethoxy or nitro, and/or the alkylenechain formed by R_(XI-1) and R_(XI-2) is possibly substituted by aradical of the formula

in which

c denotes a number 1, 2, 3 or 4,

d denotes a number 0 or 1,

R_(XI-23) and R_(XI-24) are identical or different and denote hydrogen,cycloalkyl with 3 to 6 carbon atoms, straight-chain or branched alkylwith up to 6 carbon atoms, benzyl or phenyl, which is possiblysubstituted up to 2-fold. identical or different, by halogen,trifluoromethyl, cyano, phenyl or nitro, and/or the alkylene chainformed by R_(XI-1) and R_(XI-2) is possibly substituted by aspiro-jointed radical of the formula

in which

W_(XI) denotes either an oxygen or a sulfur atom,

Y_(XI) and Y′_(XI) together form a 2- to 6-membered straight-chain orbranched alkylene chain,

e is a number 1, 2, 3, 4, 5, 6 or 7,

f denotes a number 1 or 2,

R_(XI-25), R_(XI-26), R_(XI-27), R_(XI-28), R_(XI-29), R_(XI-30) andR_(XI-31) are identical or different and denote hydrogen,trifluoromethyl, phenyl, halogen, or straight-chain or branched alkyl oralkoxy with up to 6 carbon atoms each,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form astraight-chain or branched alkyl chain with up to 6 carbon atoms,

or

R_(XI-25) and R_(XI-26) or R_(XI-27) and R_(XI-28) together form aradical of the formula

in which

W_(XI) has the meaning given above,

g is a number 1, 2, 3, 4, 5, 6 or 7,

R_(XI-32) and R_(XI-33) together form a 3- to 7-membered heterocyclethat contains an oxygen- or sulfur atom or a group of the formula SO,SO₂ or —NR_(XI-34),

in which

R_(XI-34) denotes hydrogen, phenyl, benzyl, or straight-chain orbranched alkyl with up to 4 carbon atoms.

Compounds of Formula XI and their methods of manufacture are disclosedin PCT Publication No. WO 9914174, which is incorporated herein byreference in its entirety for all purposes.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 2-aryl-substituted pyridines having the Formula(XII)

or pharmaceutically acceptable salts, enantiomers, or stereoisomers ofsaid compounds,in which

A_(XII) and E_(XII) are identical or different and stand for aryl with 6to 10 carbon atoms which is possibly substituted, up to 5-fold identicalor different, by halogen, hydroxy, trifluoromethyl, trifluoromethoxy,nitro or by straight-chain or branched alkyl, acyl, hydroxy alkyl oralkoxy with up to 7 carbon atoms each, or by a group of the formula—NR_(XII-1)R_(XII-2),

where

R_(XII-1) and R_(XII-2) are identical or different and are meant to behydrogen, phenyl or straight-chain or branched alkyl with up to 6 carbonatoms,

D_(XII) stands for straight-chain or branched alkyl with up to 8 carbonatoms, which is substituted by hydroxy,

L_(XII) stands for cycloalkyl with 3 to 8 carbon atoms or forstraight-chain or branched alkyl with up to 8 carbon atoms, which ispossibly substituted by cycloalkyl with 3 to 8 carbon atoms, or byhydroxy,

T_(XII) stands for a radical of the formula R_(XII-3)—X_(XII)— or

where

R_(XII-3) and R_(XII-4) are identical or different and are meant to becycloalkyl with 3 to 8 carbon atoms, or aryl with 6 to 10 carbon atoms,or a 5- to 7-membered aromatic, possibly benzocondensated heterocyclewith up to 3 heteroatoms from the series S, N and/or O, which arepossibly substituted. up to 3-fold identical or different, bytrifluoromethyl, trifluoromethoxy, halogen, hydroxy, carboxyl, nitro, bystraight-chain or branched alkyl, acyl, alkoxy or alkoxycarbonyl with upto 6 carbon atoms each. or by phenyl, phenoxy or phenylthio which inturn can be substituted by halogen. trifluoromethyl or trifluoromethoxy,and/or where the cycles are possibly substituted by a group of theformula —NR_(XII-7)R_(XII-8),

where

R_(XII-7) and R_(XII-8) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above,

X_(XII) is a straight-chain or branched alkyl or alkenyl with 2 to 10carbon atoms each, possibly substituted up to 2-fold by hydroxy orhalogen,

R_(XII-5) stands for hydrogen, and

R_(XII-6) means to be hydrogen, halogen, mercapto, azido,trifluoromethyl, hydroxy, trifluoromethoxy, straight-chain or branchedalkoxy with up to 5 carbon atoms, or a radical of the formulaBNR_(XII-9)R_(XII-10),

where

R_(XII-9) and R_(XII-10) are identical or different and have the meaningof R_(XII-1) and R_(XII-2) given above, or

R_(XII-5) and R_(XII-6), together with the carbon atom, form a carbonylgroup.

Compounds of Formula XII and their methods of manufacture are disclosedin EP 796846-A1, U.S. Pat. No. 6,127,383 and U.S. Pat. No. 5,925,645,all of which are incorporated herein by reference in their entiretiesfor all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XII:

-   4,6-bis-(p-fluorophenyl)-2-isopropyl-3-[(p-trifluoromethylphenyl)-(fluoro)-methyl]-5-(1-hydroxyethyl)pyridine;-   2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[4-(trifluoromethylphenyl)-fluoromethyl]-3-hydroxymethyl)pyridine;    and-   2,4-bis-(4-fluorophenyl)-6-isopropyl-5-[2-(3-trifluoromethyl    phenyl)vinyl]-3-hydroxymethyl)pyridine.

Another class of CETP inhibitors that finds utility with the presentinvention consists of compounds having the Formula (XIII)

or pharmaceutically acceptable salts, enantiomers, stereoisomers,hydrates, or solvates of said compounds, in which

R_(XIII) is a straight chain or branched C₁₋₁₀ alkyl; straight chain orbranched C₂₋₁₀ alkenyl; halogenated C₁₋₄ lower alkyl; C₃₋₁₀ cycloalkylthat may be substituted; C₅₋₈ cycloalkenyl that may be substituted;C₃₋₁₀ cycloalkyl C₁₋₁₀ alkyl that may be substituted; aryl that may besubstituted; aralkyl that may be substituted; or a 5- or 6-memberedheterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfuratoms that may be substituted,

X_(XIII-1), X_(XIII-2), X_(XIII-3), X_(XIII-4) may be the same ordifferent and are a hydrogen atom; halogen atom; C₁₋₄ lower alkyl;halogenated C₁₋₄ lower alkyl; C₁₋₄ lower alkoxy; cyano group; nitrogroup; acyl; or aryl, respectively;

Y_(XIII) is —CO—; or BSO₂—; and

Z_(XIII) is a hydrogen atom; or mercapto protective group.

Compounds of Formula XIII and their methods of manufacture are disclosedin PCT Publication No. WO 98/35937, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIIII:

-   N,N′-(dithiodi-2,1-phenylene)bis[2,2-dimethyl-propanamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-methyl-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclopentanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(3-methylbutyl)-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis[1-(2-ethylbutyl)-cyclohexanecarboxamide];-   N,N′-(dithiodi-2,1-phenylene)bis-tricyclo[3.3.1.1^(3,7)]decane-1-carboxamide;-   propanethioic acid, 2-methyl-,    S-[2[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester;-   propanethioic acid, 2,2-dimethyl-, S-[2-[[[1-(2-ethyl    butyl)cyclohexyl]carbonyl]amino]phenyl]ester; and-   ethanethioic acid,    S-[2-[[[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino]phenyl]ester.

Another class of CETP inhibitors that finds utility with the presentinvention consists of polycyclic aryl and heteroaryltertiary-heteroalkylamines having the Formula XIV

and pharmaceutically acceptable forms thereof, wherein:

n_(XIV) is an integer selected from 0 through 5;

R_(XIV-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxyalkyl, and haloalkenyloxyalkyl;

X_(XIV) is selected from the group consisting of O, H, F, S, S(O), NH,N(OH), N(alkyl), and N(alkoxy);

R_(XIV-16) is selected from the group consisting of hydrido, alkyl,alkenyl, alkynyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl,

cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxyalkyl,haloalkenyloxyalkyl, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl,

perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl, monocarboalkoxyalkyl,monocarboalkoxy, dicarboalkoxyalkyl, monocarboxamido, monocyanoalkyl,dicyanoalkyl, carboalkoxycyanoalkyl, acyl, aroyl, heteroaroyl,

heteroaryloxyalkyl, dialkoxyphosphonoalkyl, trialkylsilyl, and a spacerselected from the group consisting of a covalent single bond and alinear spacer moiety having from 1 through 4 contiguous atoms linked tothe point of bonding of an aromatic substituent selected from the groupconsisting of R_(XIV-4), R_(XIV-8), R_(XIV-9), and R_(XIV-13) to form aheterocyclyl ring having from 5 through 10 contiguous members with theprovisos that said spacer moiety is other than a covalent single bondwhen R_(XIV-2) is alkyl and there is no R_(XIV-16) wherein X is H or F;

D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) is a covalent bond, nomore than one of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) andK_(XIV-1) is O, no more than one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) is S, one of D_(XIV-1), D_(XIV-2), J_(XIV-1),J_(XIV-2) and K_(XIV-1) must be a covalent bond when two of D_(XIV-1),D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1) are O and S, and no morethan four of D_(XIV-1), D_(XIV-2), J_(XIV-1), J_(XIV-2) and K_(XIV-1)are N;

D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) areindependently selected from the group consisting of C, N, O, S and acovalent bond with the provisos that no more than one of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) is a covalent bond, nomore than one of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) andK_(XIV-2) is O, no more than one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) is S, one of D_(XIV-3), D_(XIV-4), J_(XIV-3),J_(XIV-4) and K_(XIV-2) must be a covalent bond when two of D_(XIV-3),D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2) are O and S, and no morethan four of D_(XIV-3), D_(XIV-4), J_(XIV-3), J_(XIV-4) and K_(XIV-2)and K_(XIV-2) are N;

R_(XIV-2) is independently selected from the group consisting ofhydrido, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylamino,dialkylamino, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkoxyalkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, aralkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,aloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, alkylsulfinylalkyl, alkylsulfonylalkyl,haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl,arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, cycloalkylsulfinylalkyl,cycloalkylsufonylalkyl, heteroarylsulfonylalkyl, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

R_(XIV-2) and R_(XIV-3) are taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 6 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, and a heterocyclyl having from 4 through 8 contiguous members;

R_(XIV-3) is selected from the group consisting of hydrido, hydroxy,halo, cyano, aryloxy, hydroxyalkyl, amino, alkylamino, dialkylamino,acyl, sulfhydryl, acylamido, alkoxy, alkylthio, arylthio, alkyl,alkenyl, alkynyl, aryl,

aralkyl, aryloxyalkyl, alkoxyalkyl, heteroarylthio, aralkylthio,aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aroyl,heteroaroyl, aralkylthioalkyl,

heteroaralkylthioalkyl, heteroaryloxyalkyl, alkenyloxyalkyl,alkylthioalkyl, arylthioalkyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, haloalkyl,haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, monocarboalkoxyalkyl, dicarboalkoxyalkyl,monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl, alkylsulfinyl,alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl, arylsulfinyl,arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl, aralkylsulfinyl,aralkylsulfonyl, cycloalkylsulfinyl, cycloalkylsulfonyl,cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, and diaralkoxyphosphonoalkyl;

Y_(XIV) is selected from a group consisting of a covalent single bond,(C(R_(XIV-14))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2 and (CH(R_(XIV-14)))_(gXIV)—W_(XIV-4)CH(R_(XIV-14)))_(pXIV)wherein _(gXIV) and _(pXIV) are integers independently selected from 0and 1;

R_(XIV-14) is independently selected from the group consisting ofhydrido, hydroxy, halo, cyano, aryloxy, amino, alkylamino, dialkylamino,hydroxyalkyl, acyl, aroyl, heteroaroyl, heteroaryloxyalkyl, sulfhydryl,acylamido, alkoxy, alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl,aralkyl, aryloxyalkyl, aralkoxyalkylalkoxy, alkylsulfinylalkyl,alkylsulfonylalkyl, aralkylthioalkyl, heteroaralkoxythioalkyl,alkoxyalkyl, heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl,arylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl,cycloalkenyl, cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxy, carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl,carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a heterocyclyl having from 5 through 8 contiguous members with theproviso that, when Y_(XIV) is a covalent bond, an R_(XIV-14) substituentis not attached to Y_(XIV);

R_(XIV-14) and R_(XIV-14) when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-14) and R_(XIV-14), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

W_(XIV) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XIV-14)), C(S)N(R_(XIV-14)), (R_(XIV-14))NC(O),(R_(XIV-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XIV-14)),(R_(XIV-14))NS(O)₂, and N(R_(XIV-14)) with the proviso that R_(XIV-14)is selected from other than halo and cyano;

Z_(XIV) is independently selected from a group consisting of a covalentsingle bond, (C(R_(XIV-15))₂)_(qXIV-2) wherein _(qXIV-2) is an integerselected from 1 and 2, (CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV)wherein _(jXIV) and _(kXIV) are integers independently selected from 0and 1 with the proviso that, when Z_(XIV) is a covalent single bond, anR_(XIV-15) substituent is not attached to Z_(XIV);

R_(XIV-15) is independently selected, when Z_(XIV) is(C(R_(XIV-15))₂)_(qXIV) wherein _(qXIV) is an integer selected from 1and 2, from the group consisting of hydrido, hydroxy, halo, cyano,aryloxy, amino, alkylamino, dialkylamino, hydroxyalkyl, acyl, aroyl,heteroaroyl, heteroaryloxyalkyl, sulfhydryl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, aralkoxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,aralkylthioalkyl, heteroaralkylthioalkyl, alkoxyalkyl,heteroaryloxyalkyl, alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl,cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl,cycloalkenylalkyl, haloalkyl, haloalkenyl, halocycloalkyl,halocycloalkenyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, halocycloalkenyloxyalkyl,perhaloaryl, perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl,heteroarylalkyl, heteroarylthioalkyl, heteroaralkylthioalkyl,monocarboalkoxyalkyl, dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl,haloalkylsulfonyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl,arylsulfonylalkyl, aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl,

heteroarylsulfonyl, heteroarylsulfinylalkyl, aralkylsulfinylalkyl,aralkylsulfonylalkyl, carboxy, carboxyalkyl, carboalkoxy, carboxamide,carboxamidoalkyl, carboaralkoxy, dialkoxyphosphono, diaralkoxyphosphono,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma moiety having a chain length of 3 to 6 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-4) and R_(XIV-8) toform a ring selected from the group consisting of a cycloalkenyl ringhaving from 5 through 8 contiguous members and a heterocyclyl ringhaving from 5 through 8 contiguous members, and a spacer selected from amoiety having a chain length of 2 to 5 atoms connected to the point ofbonding selected from the group consisting of R_(XIV-9) and R_(XIV-13)to form a heterocyclyl having from 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the different atoms, are takentogether to form a group selected from the group consisting of acovalent bond, alkylene, haloalkylene, and a spacer selected from agroup consisting of a moiety having a chain length of 2 to 5 atomsconnected to form a ring selected from the group of a saturatedcycloalkyl having from 5 through 8 contiguous members, a cycloalkenylhaving from 5 through 8 contiguous members, and a heterocyclyl havingfrom 5 through 8 contiguous members;

R_(XIV-15) and R_(XIV-15), when bonded to the same atom are takentogether to form a group selected from the group consisting of oxo,thiono, alkylene, haloalkylene, and a spacer selected from the groupconsisting of a moiety having a chain length of 3 to 7 atoms connectedto form a ring selected from the group consisting of a cycloalkyl havingfrom 4 through 8 contiguous members, a cycloalkenyl having from 4through 8 contiguous members, and a heterocyclyl having from 4 through 8contiguous members;

R_(XIV-15) is independently selected, when Z_(XIV) is(CH(R_(XIV-15)))_(jXIV)—W—(CH(R_(XIV-15)))_(kXIV) wherein _(jXIV) and_(kXIV) are integers independently selected from 0 and 1, from the groupconsisting of hydrido, halo, cyano, aryloxy, carboxyl, acyl, aroyl,heteroaroyl, hydroxyalkyl, heteroaryloxyalkyl, acylamido, alkoxy,alkylthio, arylthio, alkyl, alkenyl, alkynyl, aryl, aralkyl,aryloxyalkyl, alkoxyalkyl, heteroaryloxyalkyl, aralkoxyalkyl,heteroaralkoxyalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl,alkenyloxyalkyl, alkylthioalkyl, arylthioalkyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl,haloalkyl, haloalkenyl, halocycloalkyl, halocycloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl, heteroaryl, heteroarylalkyl,heteroarylthioalkyl, heteroaralkylthioalkyl, monocarboalkoxyalkyl,dicarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl, carboalkoxycyanoalkyl,alkylsulfinyl, alkylsulfonyl, haloalkylsulfinyl, haloalkylsulfonyl,arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylalkyl,aralkylsulfinyl, aralkylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, cycloalkylsulfinylalkyl, cycloalkylsufonylalkyl,heteroarylsulfonylalkyl, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylsulfinylalkyl, aralkylsulfinylalkyl, aralkylsulfonylalkyl,carboxyalkyl, carboalkoxy, carboxamide, carboxamidoalkyl, carboaralkoxy,dialkoxyphosphonoalkyl, diaralkoxyphosphonoalkyl, a spacer selected froma linear moiety having a chain length of 3 to 6 atoms connected to thepoint of bonding selected from the group consisting of R_(XIV-4) andR_(XIV-8) to form a ring selected from the group consisting of acycloalkenyl ring having from 5 through 8 contiguous members and aheterocyclyl ring having from 5 through 8 contiguous members, and aspacer selected from a linear moiety having a chain length of 2 to 5atoms connected to the point of bonding selected from the groupconsisting of R_(XIV-9) and R_(XIV-13) to form a heterocyclyl ringhaving from 5 through 8 contiguous members;

R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7), R_(XIV-8), R_(XIV-9),R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13) are independentlyselected from the group consisting of perhaloaryloxy, alkanoylalkyl,alkanoylalkoxy, alkanoyloxy, N-aryl-N-alkylamino, heterocyclylalkoxy,heterocyclylthio, hydroxyalkoxy, carboxamidoalkoxy,alkoxycarbonylalkoxy, alkoxycarbonylalkenyloxy, aralkanoylalkoxy,aralkenoyl, N-alkylcarboxamido, N-haloalkylcarboxamido,N-cycloalkylcarboxamido, N-arylcarboxamidoalkoxy, cycloalkylcarbonyl,cyanoalkoxy, heterocyclylcarbonyl, hydrido, carboxy, heteroaralkylthio,heteroaralkoxy, cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy,heterocyclyloxy, aralkylaryl, aralkyl, aralkenyl, aralkynyl,heterocyclyl, perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl,aralkylsulfinyl, aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl; haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that there are one to fivenon-hydrido ring substituents R_(XIV-4), R_(XIV-5), R_(XIV-6),R_(XIV-7), and R_(XIV-8) present, that there are one to five non-hydridoring substituents R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), andR_(XIV-13) present, and R_(XIV-4), R_(XIV-5), R_(XIV-6), R_(XIV-7),R_(XIV-8), R_(XIV-9), R_(XIV-10), R_(XIV-11), R_(XIV-12), and R_(XIV-13)are each independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XIV-4) and R_(XIV-5), R_(XIV-5) and R_(XIV-6), R_(XIV-6) andR_(XIV-7), R_(XIV-7) and R_(XIV-8), R_(XIV-8) and R_(XIV-9), R_(XIV-9)and R_(XIV-10), R_(XIV-10) and R_(XIV-11), R_(XIV-11) and R_(XIV-12),and R_(XIV-12) and R_(XIV-13) are independently selected to form spacerpairs wherein a spacer pair is taken together to form a linear moietyhaving from 3 through 6 contiguous atoms connecting the points ofbonding of said spacer pair members to form a ring selected from thegroup consisting of a cycloalkenyl ring having 5 through 8 contiguousmembers, a partially saturated heterocyclyl ring having 5 through 8contiguous members, a heteroaryl ring having 5 through 6 contiguousmembers, and an aryl with the provisos that no more than one of thegroup consisting of spacer pairs R_(XIV-4) and R_(XIV-5), R_(XIV-5) andR_(XIV-6), R_(XIV-6) and R_(XIV-7), and R_(XIV-7) and R_(XIV-8) are usedat the same time and that no more than one of the group consisting ofspacer pairs R_(XIV-9) and R_(XIV-10), R_(XIV-10) and R_(XIV-11),R_(XIV-11) and R_(XIV-12), and R_(XIV-12) and R_(XIV-13) are used at thesame time;

R_(XIV-4) and R_(XIV-9), R_(XIV-4) and R_(XIV-13), R_(XIV-8) andR_(XIV-9), and R_(XIV-8) and R_(XIV-13) are independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XIV-4) and R_(XIV-9), R_(XIV-4)and R_(XIV-13), R_(XIV-8) and R_(XIV-9), and R_(XIV-8) and R_(XIV-13) isused at the same time.

Compounds of Formula XIV and their methods of manufacture are disclosedin PCT Publication No. WO 00/18721, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XIV:

-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropyl    phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethyl    phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethymethyl]amino]-1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropyl    phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][(3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butyl    phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethyl    phenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-([3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethyl    phenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethyl    phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethyl    phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;    and-   3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of substituted N-Aliphatic-N-Aromatictertiary-Heteroalkylamines having the Formula XV

and pharmaceutically acceptable forms thereof, wherein:

n_(XV) is an integer selected from 1 through 2;

A_(XV) and Q_(XV) are independently selected from the group consistingof—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uXV)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV-)H.

with the provisos that one of A_(XV) and Q_(XV) must be AQ-1 and thatone of A_(XV) and Q_(XV) must be selected from the group consisting ofAQ-2 and—CH₂(CR_(XV-37)R_(XV-38))_(vXV)—(CR_(XV-33)R_(XV-34))_(uxv)-T_(XV)-(CR_(XV-35)R_(XV-36))_(wXV)—H;

T_(XV) is selected from the group consisting of a single covalent bond,O, S, S(O), S(O)₂, C(R_(XV-33))—C(R_(XV-35)), and

C≡C;

_(vXV) is an integer selected from 0 through 1 with the proviso that_(vXV) is 1 when any one of R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) is aryl or heteroaryl;

_(uXV) and _(wXV) are integers independently selected from 0 through 6;

A_(XV-1) is C(R_(XV-30));

D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) are independentlyselected from the group consisting of C, N, O, S and a covalent bondwith the provisos that no more than one of D_(XV-1), D_(XV-2), J_(XV-1),J_(XV-2), and K_(XV-1) is a covalent bond, no more than one of D_(XV-1),D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is O, no more than one ofD_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1) is S, one ofD_(XV-1), D_(XV-2), J_(XV-1), J_(XV-1), and K_(XV-2) must be a covalentbond when two of D_(XV-1), D_(XV-2), J_(XV-1), J_(XV-2), and K_(XV-1)are O and S, and no more than four of D_(XV-1), D_(XV-2), J_(XV-1),J_(XV-2), and K_(XV-1) are N;

B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C, C(R_(XV-30)),N, O, S and a covalent bond with the provisos that no more than 5 ofB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are a covalent bond, no more than two of B_(XV-1), B_(XV-2), D_(XV-3),D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2) are O, no more than two ofB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are S, no more than two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4),J_(XV-3), J_(XV-4), and K_(XV-2) are simultaneously O and S, and no morethan two of B_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4),and K_(XV-2) are N;

B_(XV-1) and D_(XV-3), D_(XV-3) and J_(XV-3), J_(XV-3) and K_(XV-2),K_(XV-2) and J_(XV-4), J_(XV-4) and D_(XV-4), and D_(XV-4) and B_(XV-2)are independently selected to form an in-ring spacer pair wherein saidspacer pair is selected from the group consisting ofC(R_(XV-33))═C(R_(XV-35)) and N═N with the provisos that AQ-2 must be aring of at least five contiguous members, that no more than two of thegroup of said spacer pairs are simultaneously C(R_(XV-33))═C(R_(XV-35))and that no more than one of the group of said spacer pairs can be N═Nunless the other spacer pairs are other than C(R_(XV-33))═C(R_(XV-35)),O, N, and S;

R_(XV-1) is selected from the group consisting of haloalkyl andhaloalkoxymethyl;

R_(XV-2) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, haloalkoxy, haloalkoxyalkyl, perhaloaryl,perhaloaralkyl, perhaloaryloxyalkyl and heteroaryl;

R_(XV-3) is selected from the group consisting of hydrido, aryl, alkyl,alkenyl, haloalkyl, and haloalkoxyalkyl;

Y_(XV) is selected from the group consisting of a covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2 and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

Z_(XV) is selected from the group consisting of covalent single bond,(CH₂)_(q) wherein q is an integer selected from 1 through 2, and(CH₂)_(j)—O—(CH₂)_(k) wherein j and k are integers independentlyselected from 0 through 1;

R_(XV-4), R_(XV-8), R_(XV-9) and R_(XV-13) are independently selectedfrom the group consisting of hydrido, halo, haloalkyl, and alkyl;

R_(XV-30) is selected from the group consisting of hydrido, alkoxy,alkoxyalkyl, halo, haloalkyl, alkylamino, alkylthio, alkylthioalkyl,alkyl, alkenyl, haloalkoxy, and haloalkoxyalkyl with the proviso thatR_(XV-30) is selected to maintain the tetravalent nature of carbon,trivalent nature of nitrogen, the divalent nature of sulfur, and thedivalent nature of oxygen;

R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring linear spacer connecting the A_(XV-1)-carbon at the point ofattachment of R_(XV-30) to the point of bonding of a group selected fromthe group consisting of R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-31), andR_(XV-32) wherein said intra-ring linear spacer is selected from thegroup consisting of a covalent single bond and a spacer moiety havingfrom 1 through 6 contiguous atoms to form a ring selected from the groupconsisting of a cycloalkyl having from 3 through 10 contiguous members,a cycloalkenyl having from 5 through 10 contiguous members, and aheterocyclyl having from 5 through 10 contiguous members;

R_(XV-30), when bonded to A_(XV-1), is taken together to form anintra-ring branched spacer connecting the A_(XV-1)-carbon at the pointof attachment of R_(XV-30) to the points of bonding of each member ofany one of substituent pairs selected from the group consisting ofsubstituent pairs R_(XV-10) and R_(XV-11), R_(XV-10) and R_(XV-31),R_(XV-10) and R_(XV-32), R_(XV-10) and R_(XV-12), R_(XV-11) andR_(XV-31), R_(XV-11) and R_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-31)and R_(XV-32), R_(XV-31) and R_(XV-12) and R_(XV-32) and R_(XV-12) andwherein said intra-ring branched spacer is selected to form two ringsselected from the group consisting of cycloalkyl having from 3 through10 contiguous members, cycloalkenyl having from 5 through 10 contiguousmembers, and heterocyclyl having from 5 through 10 contiguous members;

R_(XV-4), R_(XV-5), R_(XV-6), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10),R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), R_(XV-32), R_(XV-33),R_(XV-34), R_(XV-35), and R_(XV-36) are independently selected from thegroup consisting of hydrido, carboxy, heteroaralkylthio, heteroaralkoxy,cycloalkylamino, acylalkyl, acylalkoxy, aroylalkoxy, heterocyclyloxy,aralkylaryl, aralkyl, aralkenyl, aralkynyl, heterocyclyl,perhaloaralkyl, aralkylsulfonyl, aralkylsulfonylalkyl, aralkylsulfinyl,aralkylsulfinylalkyl, halocycloalkyl, halocycloalkenyl,cycloalkylsulfinyl, cycloalkylsulfinylalkyl, cycloalkylsulfonyl,cycloalkylsulfonylalkyl, heteroarylamino,N-heteroarylamino-N-alkylamino, heteroarylaminoalkyl, haloalkylthio,alkanoyloxy, alkoxy, alkoxyalkyl, haloalkoxylalkyl, heteroaralkoxy,cycloalkoxy, cycloalkenyloxy, cycloalkoxyalkyl, cycloalkylalkoxy,

cycloalkenyloxyalkyl, cycloalkylenedioxy, halocycloalkoxy,

halocycloalkoxyalkyl, halocycloalkenyloxy, halocycloalkenyloxyalkyl,hydroxy, amino, thio, nitro, lower alkylamino, alkylthio,alkylthioalkyl, arylamino, aralkylamino, arylthio, arylthioalkyl,heteroaralkoxyalkyl, alkylsulfinyl, alkylsulfinylalkyl,arylsulfinylalkyl, arylsulfonylalkyl, heteroarylsulfinylalkyl,heteroarylsulfonylalkyl, alkylsulfonyl, alkylsulfonylalkyl,haloalkylsulfinylalkyl, haloalkylsulfonylalkyl, alkylsulfonamido,alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkylamidosulfonyl, monoarylamidosulfonyl, arylsulfonamido,diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl, arylsulfinyl,arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heterocyclylsulfonyl, heterocyclylthio, alkanoyl, alkenoyl, aroyl,heteroaroyl, aralkanoyl, heteroaralkanoyl, haloalkanoyl, alkyl, alkenyl,alkynyl, alkenyloxy, alkenyloxyalky, alkylenedioxy, haloalkylenedioxy,cycloalkyl, cycloalkylalkanoyl, cycloalkenyl, lower cycloalkylalkyl,lower cycloalkenylalkyl, halo, haloalkyl, haloalkenyl, haloalkoxy,hydroxyhaloalkyl, hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl,haloalkoxyalkyl, aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl,saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,alkylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the provisos that R_(XV-4), R_(XV-5),R_(XV-4), R_(XV-7), R_(XV-8), R_(XV-9), R_(XV-10), R_(XV-1), R_(XV-12),R_(XV-13), R_(XV-3), R_(XV-32), R_(XV-33), R_(XV-34), R_(XV-35), andR_(XV-36) are each independently selected to maintain the tetravalentnature of carbon, trivalent nature of nitrogen, the divalent nature ofsulfur, and the divalent nature of oxygen, that no more than three ofthe R_(XV-33) and R_(XV-34) substituents are simultaneously selectedfrom other than the group consisting of hydrido and halo, and that nomore than three of the R_(XV-35) and R_(XV-36) substituents aresimultaneously selected from other than the group consisting of hydridoand halo;

R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), andR_(XV-32) are independently selected to be oxo with the provisos thatB_(XV-1), B_(XV-2), D_(XV-3), D_(XV-4), J_(XV-3), J_(XV-4), and K_(XV-2)are independently selected from the group consisting of C and S, no morethan two of R_(XV-9), R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13),R_(XV-31), and R_(XV-32) are simultaneously oxo, and that R_(XV-9),R_(XV-10), R_(XV-11), R_(XV-12), R_(XV-13), R_(XV-31), and R_(XV-32) areeach independently selected to maintain the tetravalent nature ofcarbon, trivalent nature of nitrogen, the divalent nature of sulfur, andthe divalent nature of oxygen;

R_(XV-4) and R_(XV-5), R_(XV-5) and R_(XV-6), R_(XV-6) and R_(XV-7),R_(XV-7) and R_(XV-8), R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-11),R_(XV-11) and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) andR_(XV-12), and R_(XV-12) and R_(XV-13) are independently selected toform spacer pairs wherein a spacer pair is taken together to form alinear moiety having from 3 through 6 contiguous atoms connecting thepoints of bonding of said spacer pair members to form a ring selectedfrom the group consisting of a cycloalkenyl ring having 5 through 8contiguous members, a partially saturated heterocyclyl ring having 5through 8 contiguous members, a heteroaryl ring having 5 through 6contiguous members, and an aryl with the provisos that no more than oneof the group consisting of spacer pairs R_(XV-4) and R_(XV-5), R_(XV-5)and R_(XV-6), R_(XV-6) and R_(XV-7), R_(XV-7) and R_(XV-8) is used atthe same time and that no more than one of the group consisting ofspacer pairs R_(XV-9) and R_(XV-10), R_(XV-10) and R_(XV-1), R_(XV-11)and R_(XV-31), R_(XV-31) and R_(XV-32), R_(XV-32) and R_(XV-12), andR_(XV-12) and R_(XV-13) are used at the same time;

R_(XV-9) and R_(XV-11), R_(XV-9) and R_(XV-12), R_(XV-9) and R_(XV-13),R_(XV-9) and R_(XV-31), R_(XV-9) and R_(XV-32), R_(XV-10) and R_(XV-12),R_(XV-10) and R_(XV-13), R_(XV-10) and R_(XV-31), R_(XV-10) andR_(XV-32), R_(XV-11) and R_(XV-12), R_(XV-11) and R_(XV-13), R_(XV-11)and R_(XV-32), R_(XV-12) and R_(XV-31), R_(XV-13) and R_(XV-31), andR_(XV-13) and R_(XV-32) are independently selected to form a spacer pairwherein said spacer pair is taken together to form a linear spacermoiety selected from the group consisting of a covalent single bond anda moiety having from 1 through 3 contiguous atoms to form a ringselected from the group consisting of a cycloalkyl having from 3 through8 contiguous members, a cycloalkenyl having from 5 through 8 contiguousmembers, a saturated heterocyclyl having from 5 through 8 contiguousmembers and a partially saturated heterocyclyl having from 5 through 8contiguous members with the provisos that no more than one of said groupof spacer pairs is used at the same time;

R_(XV-37) and R_(XV-38) are independently selected from the groupconsisting of hydrido, alkoxy, alkoxyalkyl, hydroxy, amino, thio, halo,haloalkyl, alkylamino, alkylthio, alkylthioalkyl, cyano, alkyl, alkenyl,haloalkoxy, and haloalkoxyalkyl.

Compounds of Formula XV and their methods of manufacture are disclosedin PCT Publication No. WO 00/18723, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XV:

-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethyl    phenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethyl    phenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethyl    phenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethyl    phenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl](3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclopentylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-isopropylphenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl](cyclopropylmethy)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(2,3-dichlorophenoxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl](cyclopropylmethyl)amino]-1,1,1-triflouro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy]phenyl](cyclohexyl    methyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[(3-(3-trifluoromethoxybenzyloxy)phenyl](cyclopropylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy]phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethoxybenzyloxy)phenyl][3-(1, 1, 2,    2-tetrafluoroethoxy)-cyclohexylmethyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethyl    benzyloxy)phenyl](cyclohexylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopentylmethyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl](cyclopropyl    methyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethylbenzyloxy)phenyl][(3-trifluoromethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethyl    benzyloxy)phenyl][(3-pentafluoroethyl)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethyl    benzyloxy)phenyl][(3-trifluoromethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[3-(3-trifluoromethyl    benzyloxy)phenyl][3-(1,1,2,2-tetrafluoroethoxy)cyclohexyl-methyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](cyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](4-methylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl]phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[((3-trifluoromethyl)phenyl]-methyl)[3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-methylphenoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-cyclohexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl]phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifloromethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-isopropoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl](3-cyclopentyloxycyclohexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl]phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-isopropoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-cyclopentyloxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-phenoxycyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethylcyclohexyl)amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(4-chloro-3-ethylphenoxy)cyclo-hexyl]amino]-1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl][3-(1,1,2,2-tetrafluoroethoxy)cyclo-hexyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-pentafluoroethylcyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(2-trifluoromethyl)pyrid-6-yl]methyl](3-trifluoromethoxycyclohexyl)-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)propyl]-amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-pentafluoroethyl)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-di-fluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(4-chloro-3-ethylphenoxy)-2,2,-difluropropyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-pentafluoroethyl)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[(3-trifluoromethoxy)phenyl]methyl][3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]]3-(isopropoxy)propyl]amino]-1,1,1-trifluoro-2-propanol;    and-   3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-(phenoxy)propyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of (R)-chiral halogenated 1-substitutedamino-(n+I)-alkanols having the Formula XVI

and pharmaceutically acceptable forms thereof, wherein:

n_(XVI) is an integer selected from 1 through 4;

X_(XVI) is oxy;

R_(XVI-1) is selected from the group consisting of haloalkyl,haloalkenyl, haloalkoxymethyl, and haloalkenyloxymethyl with the provisothat R_(XVI-1) has a

higher Cahn-Ingold-Prelog stereochemical system ranking than bothR_(XVI-2) and (CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI) wherein A_(XVI) isFormula XVI-(II) and Q is Formula XVI-(III);

R_(XVI-16) is selected from the group consisting of hydrido, alkyl,acyl, aroyl, heteroaroyl, trialkylsilyl, and a spacer selected from thegroup consisting of a covalent single bond and a linear spacer moietyhaving a chain length of 1 to 4 atoms linked to the point of bonding ofany aromatic substituent selected from the group consisting ofR_(XVI-4), R_(XVI-8), R_(XVI-9), and R_(XVI-13) to form a heterocyclylring having from 5 through 10 contiguous members;

D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one of D_(XVI-1),D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is a covalent bond, nomore than one D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1)is be O, no more than one of D_(XVI-1). D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) is S, one of D_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2)and K_(XVI-1) must be a covalent bond when two of D_(XVI-1), D_(XVI-2),J_(XVI-1), J_(XVI-2) and K_(XVI-1) are O and S, and no more than four ofD_(XVI-1), D_(XVI-2), J_(XVI-1), J_(XVI-2) and K_(XVI-1) is N;

D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areindependently selected from the group consisting of C, N, O, S andcovalent bond with the provisos that no more than one is a covalentbond, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) andK_(XVI-2) is O, no more than one of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) is S, no more than two of D_(XVI-3), D_(XVI-4),J_(XVI-3), J_(XVI-4) and K_(XVI-2) is O and S, one of D_(XVI-3),D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) must be a covalent bondwhen two of D_(XVI-3), D_(XVI-4), J_(XVI-3), J_(XVI-4) and K_(XVI-2) areO and S, and no more than four of D_(XVI-3), D_(XVI-4), J_(XVI-3),J_(XVI-4) and K_(XVI-2) are N;

R_(XVI-2) is selected from the group consisting of hydrido, aryl,aralkyl, alkyl, alkenyl, alkenyloxyalkyl, haloalkyl, haloalkenyl,halocycloalkyl, haloalkoxy, haloalkoxyalkyl, haloalkenyloxyalkyl,halocycloalkoxy, halocycloalkoxyalkyl, perhaloaryl, perhaloaralkyl,perhaloaryloxyalkyl, heteroaryl, dicyanoalkyl, andcarboalkoxycyanoalkyl, with the proviso that R_(XVI-2) has a lowerCahn-Ingold-Prelog system ranking than both R_(XVI-1), and(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI);

R_(XVI-3) is selected from the group consisting of hydrido, hydroxy,cyano, aryl, aralkyl, acyl, alkoxy, alkyl, alkenyl, alkoxyalkyl,heteroaryl, alkenyloxyalkyl, haloalkyl, haloalkenyl, haloalkoxy,haloalkoxyalkyl, haloalkenyloxyalkyl, monocyanoalkyl, dicyanoalkyl,carboxamide, and carboxamidoalkyl, with the provisos that(CHR_(XVI-3))_(n)—N(A_(XVI))Q_(XVI) has a lower Cahn-Ingold-Prelogstereochemical system ranking than R_(XVI-1) and a higherCahn-Ingold-Prelog stereochemical system ranking than R_(XVI-2);

Y_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-4))₂)_(q) wherein q is an integer selected from 1 and 2 and(CH(R_(XVI-14)))_(g)—W_(XVI-4)CH(R_(XVI-14)))_(p) wherein g and p areintegers independently selected from 0 and 1;

R_(XVI-14) is selected from the group consisting of hydrido, hydroxy,cyano, hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

Z_(XVI) is selected from a group consisting of a covalent single bond,(C(R_(XVI-15))₂)_(q), wherein q is an integer selected from 1 and 2, and(CH(R_(XVI-15)))_(j)—W_(XVI)—(CH(R_(XVI-15)))_(k) wherein j and k areintegers independently selected from 0 and 1;

W_(XVI) is selected from the group consisting of O, C(O), C(S),C(O)N(R_(XVI-14)), C(S)N(R_(XVI-14)), (R_(XVI-14))NC(O),(R_(XVI-14))NC(S), S, S(O), S(O)₂, S(O)₂N(R_(XVI-14)),(R_(XVI-14))NS(O)₂, and N(R_(XVI-14)) with the proviso that R_(XVI-14)is other than cyano;

R_(XVI-15) is selected, from the group consisting of hydrido, cyano,hydroxyalkyl, acyl, alkoxy, alkyl, alkenyl, alkynyl, alkoxyalkyl,haloalkyl, haloalkenyl, haloalkoxy, haloalkoxyalkyl,haloalkenyloxyalkyl, monocarboalkoxyalkyl, monocyanoalkyl, dicyanoalkyl,carboalkoxycyanoalkyl, carboalkoxy, carboxamide, and carboxamidoalkyl;

R_(XVI-4), R_(XVI-5), R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9),R_(XVI-10), R_(XVI-11), R_(XVI-12), and R_(XVI-13) are independentlyselected from the group consisting of hydrido, carboxy,heteroaralkylthio, heteroaralkoxy, cycloalkylamino, acylalkyl,acylalkoxy, aroylalkoxy, heterocyclyloxy, aralkylaryl, aralkyl,aralkenyl, aralkynyl, heterocyclyl, perhaloaralkyl, aralkylsulfonyl,aralkylsulfonylalkyl, aralkylsulfinyl, aralkylsulfinylalkyl,halocycloalkyl, halocycloalkenyl, cycloalkylsulfinyl,cycloalkylsulfinylalkyl, cycloalkylsulfonyl, cycloalkylsulfonylalkyl,heteroarylamino, N-heteroarylamino-N-alkylamino, heteroaralkyl,heteroarylaminoalkyl, haloalkylthio, alkanoyloxy, alkoxy, alkoxyalkyl,haloalkoxylalkyl, heteroaralkoxy, cycloalkoxy, cycloalkenyloxy,cycloalkoxyalkyl, cycloalkylalkoxy, cycloalkenyloxyalkyl,cycloalkylenedioxy, halocycloalkoxy, halocycloalkoxyalkyl,halocycloalkenyloxy, halocycloalkenyloxyalkyl, hydroxy, amino, thio,nitro, lower alkylamino, alkylthio, alkylthioalkyl, arylamino,aralkylamino, arylthio, arylthioalkyl, heteroaralkoxyalkyl,alkylsulfinyl, alkylsulfinylalkyl, arylsulfinylalkyl, arylsulfonylalkyl,heteroarylsulfinylalkyl, heteroarylsulfonylalkyl, alkylsulfonyl,alkylsulfonylalkyl, haloalkylsulfinylalkyl, haloalkylsulfonylalkyl,alkylsulfonamido, alkylaminosulfonyl, amidosulfonyl, monoalkylamidosulfonyl, dialkyl, amidosulfonyl, monoarylamidosulfonyl,arylsulfonamido, diarylamidosulfonyl, monoalkyl monoaryl amidosulfonyl,arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclylsulfonyl, heterocyclylthio, alkanoyl,alkenoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl,haloalkanoyl, alkyl, alkenyl, alkynyl, alkenyloxy, alkenyloxyalky,alkylenedioxy, haloalkylenedioxy, cycloalkyl, cycloalkylalkanoyl,cycloalkenyl, lower cycloalkylalkyl, lower cycloalkenylalkyl, halo,haloalkyl, haloalkenyl, haloalkoxy, hydroxyhaloalkyl,

hydroxyaralkyl, hydroxyalkyl, hydoxyheteroaralkyl, haloalkoxyalkyl,aryl, heteroaralkynyl, aryloxy, aralkoxy, aryloxyalkyl, saturatedheterocyclyl, partially saturated heterocyclyl, heteroaryl,heteroaryloxy, heteroaryloxyalkyl, arylalkenyl, heteroarylalkenyl,carboxyalkyl, carboalkoxy, alkoxycarboxamido, alkylamidocarbonylamido,arylamidocarbonylamido, carboalkoxyalkyl, carboalkoxyalkenyl,carboaralkoxy, carboxamido, carboxamidoalkyl, cyano, carbohaloalkoxy,phosphono, phosphonoalkyl, diaralkoxyphosphono, anddiaralkoxyphosphonoalkyl with the proviso that R_(XVI-4), R_(XVI-5),R_(XVI-6), R_(XVI-7), R_(XVI-8), R_(XVI-9), R_(XVI-10), R_(XVI-11),R_(XVI-12), and R_(XVI-13) are each independently selected to maintainthe tetravalent nature of carbon, trivalent nature of nitrogen, thedivalent nature of sulfur, and the divalent nature of oxygen;

R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), R_(XVI-7) and R_(XVI-8), R_(XVI-9) and R_(XVI-10), R_(XVI-10)and R_(XVI-11), R_(XVI-11) and R_(XVI-12), and R_(XVI-12) and R_(XIV-13)are independently selected to form spacer pairs wherein a spacer pair istaken together to form a linear moiety having from 3 through 6contiguous atoms connecting the points of bonding of said spacer pairmembers to form a ring selected from the group consisting of acycloalkenyl ring having 5 through 8 contiguous members, a partiallysaturated heterocyclyl ring having 5 through 8 contiguous members, aheteroaryl ring having 5 through 6 contiguous members, and an aryl withthe provisos that no more than one of the group consisting of spacerpairs R_(XVI-4) and R_(XVI-5), R_(XVI-5) and R_(XVI-6), R_(XVI-6) andR_(XVI-7), and R_(XVI-7) and R_(XVI-8) is used at the same time and thatno more than one of the group consisting of spacer pairs R_(XIV-9) andR_(XVI-10), R_(XVI-10) and R_(XVI-11), R_(XVI-11) and R_(XVI-12), andR_(XVI-12) and R_(XVI-13) can be used at the same time;

R_(XVI-4) and R_(XVI-9), R_(XVI-4) and R_(XVI-13), R_(XVI-8) andR_(XVI-9), and R_(XVI-8) and R_(XVI-13) is independently selected toform a spacer pair wherein said spacer pair is taken together to form alinear moiety wherein said linear moiety forms a ring selected from thegroup consisting of a partially saturated heterocyclyl ring having from5 through 8 contiguous members and a heteroaryl ring having from 5through 6 contiguous members with the proviso that no more than one ofthe group consisting of spacer pairs R_(XVI-4) and R_(XVI-9), R_(XVI-4)and R_(XVI-13), R_(XVI-8) and R_(XVI-9), and R_(XVI-8) and R_(XVI-13) isused at the same time.

Compounds of Formula XVI and their methods of manufacture are disclosedin PCT Publication No. WO 00/18724, which is incorporated herein byreference in its entirety for all purposes.

In a preferred embodiment, the CETP inhibitor is selected from thefollowing compounds of Formula XVI:

-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(1, 1, 2,    2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol:-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2,-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifuoromethylthio)phenoxy]phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3(pentafluoroethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-([3-(trifluoromethyl)-phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(pentafluoroethyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(pentafluoroethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(pentafluoroethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;

(2R)-3-[[3-(4-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;

-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][13-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[3-(heptafluoropropyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1,-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-dimethylphenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[[3,5-difluorophenyl]methoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(heptafluoropropyl)phenyl]methyl][3-[cyclohexylmethoxy]phenyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[3-(heptafluoropropyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[3-(heptafluoropropyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (1R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-3-propanol;-   (2R)-3-[[3-(4-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino,phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-3-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl)]3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-5-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl    4-pyridyloxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-5-(trifluoromethyl)_(y)    phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-trifluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-isopropylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-cyclopropylphenoxy)phenyl][[2-flouro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-(2-furyl)phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2,3-dichlorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-fluorophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[344-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-fluoro-5-bromophenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(4-chloro-3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(1,1,2,2-tetrafluoroethoxy)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(pentafluoroethyl)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3,5-dimethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]-methyl]amino]-1,1,1]-trifluoro-2-propanol;-   (2R)-3-[[3-(3-ethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-t-butylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-methylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(5,6,7,8-tetrahydro-2-naphthoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(phenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-[3-(N,N-dimethylamino)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethoxy)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (3R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethyl)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl](3-[[3,5-dimethylphenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3-(trifluoromethylthio)phenyl]methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[[3,5-difluorophenyl]-methoxy]phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[2-fluoro-4-(trifluoromethyl)phenyl]methyl][3-[cyclohexylmethoxy]-phenyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-difluoromethoxy-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(2-trifluoromethyl-4-pyridyloxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[3-(3-difluoromethoxyphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)-phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;-   (2R)-3-[[[3-(3-trifluoromethylthio)phenoxy]phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol;    and-   (2R)-3-[[3-(4-chloro-3-trifluoromethylphenoxy)phenyl][[2-fluoro-4-(trifluoromethyl)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol.

Another class of CETP inhibitors that finds utility with the presentinvention consists of quinolines of Formula XVII

and pharmaceutically acceptable forms thereof, wherein:

A_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with up to five identical or differentsubstituents in the form of a halogen, nitro, hydroxyl, trifluoromethyl,trifluoromethoxy or a straight-chain or branched alkyl, acyl,hydroxyalkyl or alkoxy containing up to 7 carbon atoms each, or in theform of a group according to the formula —NR_(XVII-4)R_(XVII-5), wherein

R_(XVII-4) and R_(XVII-5) are identical or different and denote ahydrogen, phenyl or a straight-chain or branched alkyl containing up to6 carbon atoms,

D_(XVII) denotes an aryl containing 6 to 10 carbon atoms, which isoptionally substituted with a phenyl, nitro, halogen, trifluoromethyl ortrifluoromethoxy, or a radical according to the formula

wherein

R_(XVII-6), R_(XVII-7), R_(XVII-10) denote, independently from oneanother, a cycloalkyl containing 3 to 6 carbon atoms, or an arylcontaining 6 to 10 carbon atom or a 5- to 7-membered, optionallybenzo-condensed, saturated or unsaturated, mono-, bi- or tricyclicheterocycle containing up to 4 heteroatoms from the series of S, Nand/or O, wherein the rings are optionally substituted, in the case ofthe nitrogen-containing rings also via the N function, with up to fiveidentical or different substituents in the form of a halogen,trifluoromethyl, nitro, hydroxyl, cyano, carboxyl, trifluoromethoxy, astraight-chain or branched acyl, alkyl, alkylthio, alkylalkoxy, alkoxyor alkoxycarbonyl containing up to 6 carbon atoms each, an aryl ortrifluoromethyl-substituted aryl containing 6 to 10 carbon atoms each,or an optionally benzo-condensed, aromatic 5- to 7-membered heterocyclecontaining up to 3 heteroatoms from the series of S, N and/or O, and/orin the form of a group according to the formula —OR_(XVII-11),—SR_(XVII-12), —SO₂R_(XVII-13), or —NR_(XVII-14)R_(XVII-15);

R_(XVII-11), R_(XVII-12), and R_(XVII-13) denote, independently from oneanother, an aryl containing 6 to 10 carbon atoms, which is in turnsubstituted with up to two identical or different substituents in theform of a phenyl, halogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms,

R_(XVII-14) and R_(XVII-15) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-5) given above, or

R_(XVII-6) and/or R_(XVII-7) denote a radical according to the formula

R_(XVII-8) denotes a hydrogen or halogen, and

R_(XVII-9) denotes a hydrogen, halogen, azido, trifluoromethyl,hydroxyl, trifluoromethoxy, a straight-chain or branched alkoxy or alkylcontaining up to 6 carbon atoms each, or a radical according to theformula NR_(XVII-16)R_(XVII-17);

R_(XVII-16) and R_(XVII-17) are identical or different and have themeaning of R_(XVII-4) and R_(XVII-5) above; or

R_(XVII-8) and R_(XVII-9) together form a radical according to theformula ═O or ═NR_(XVII-18);

R_(XVII-18) denotes a hydrogen or a straight-chain or branched alkyl,alkoxy or acyl containing up to 6 carbon atoms each;

L_(XVII) denotes a straight-chain or branched alkylene or alkenylenechain containing up to 8 carbon atoms each, which are optionallysubstituted with up to two hydroxyl groups;

T_(XVII) and X_(XVII) are identical or different and denote astraight-chain or branched alkylene chain containing up to 8 carbonatoms; or

T_(XVII) and X_(XVII) denotes a bond;

V_(XVII) denotes an oxygen or sulfur atom or —NR_(XVII-19);

R_(XVII-19) denotes a hydrogen or a straight-chain or branched alkylcontaining up to 6 carbon atoms or a phenyl;

E_(XVII) denotes a cycloalkyl containing 3 to 8 carbon atoms, or astraight-chain or branched alkyl containing up to 8 carbon atoms, whichis optionally substituted with a cycloalkyl containing 3 to 8 carbonatoms or a hydroxyl, or a phenyl, which is optionally substituted with ahalogen or trifluoromethyl;

R_(XVII-1) and R_(XVII-2) are identical or different and denote acycloalkyl containing 3 to 8 carbon atoms, hydrogen, nitro, halogen,trifluoromethyl, trifluoromethoxy, carboxy, hydroxy, cyano, astraight-chain or branched acyl, alkoxycarbonyl or alkoxy with up to 6carbon atoms, or NR_(XVII-20)R_(XVII-21);

R_(XVII-20) and R_(XVII-21) are identical or different and denotehydrogen, phenyl, or a straight-chain or branched alkyl with up to 6carbon atoms; and or

R_(XVII-1) and/or R_(XVII-2) are straight-chain or branched alkyl withup to 6 carbon atoms, optionally substituted with halogen,trifluoromethoxy, hydroxy, or a straight-chain or branched alkoxy withup to 4 carbon atoms, aryl containing 6-10 carbon atoms optionallysubstituted with up to five of the same or different substituentsselected from halogen, cyano, hydroxy, trifluoromethyl,trifluoromethoxy, nitro, straight-chain or branched alkyl, acyl,hydroxyalkyl, alkoxy with up to 7 carbon atoms andNR_(XVII-22)R_(XVII-23;)

R_(XVII-22) and R_(XVII-23) are identical or different and denotehydrogen, phenyl or a straight-chain or branched alkyl up to 6 carbonatoms; and/or

R_(XVII-1) and R_(XVII-2) taken together form a straight-chain orbranched alkene or alkane with up to 6 carbon atoms optionallysubstituted with halogen, trifluoromethyl, hydroxy or straight-chain orbranched alkoxy with up to 5 carbon atoms;

R_(XVII-3) denotes hydrogen, a straight-chain or branched acyl with upto 20 carbon atoms, a benzoyl optionally substituted with halogen,trifluoromethyl, nitro or trifluoromethoxy, a straight-chained orbranched fluoroacyl with up to 8 carbon atoms and 7 fluoro atoms, acycloalkyl with 3 to 7 carbon atoms, a straight chained or branchedalkyl with up to 8 carbon atoms optionally substituted with hydroxyl, astraight-chained or branched alkoxy with up to 6 carbon atoms optionallysubstituted with phenyl which may in turn be substituted with halogen,nitro, trifluoromethyl, trifluoromethoxy, or phenyl or a tetrazolsubstituted phenyl, and/or an alkyl that is optionally substituted witha group according to the formula —OR_(XVII-24);

R_(XVII-24) is a straight-chained or branched acyl with up to 4 carbonatoms or benzyl.

Compounds of Formula XVII and their methods of manufacture are disclosedin PCT Publication No. WO 98/39299, which is incorporated herein byreference in its entirety for all purposes.

Another class of CETP inhibitors that finds utility with the presentinvention consists of 4-Phenyltetrahydroquinolines of Formula XVIII

N oxides thereof, and pharmaceutically acceptable forms thereof,wherein:

A_(XVIII) denotes a phenyl optionally substituted with up to twoidentical or different substituents in the form of halogen,trifluoromethyl or a straight-chain or branched alkyl or alkoxycontaining up to three carbon atoms;

D_(XVIII) denotes the formula

R_(XVIII-5) and R_(XVIII-6) are taken together to form ═O; or

R_(XVIII-5) denotes hydrogen and R_(XVIII-6) denotes halogen orhydrogen; or

R_(XVIII-5) and R_(XVIII-6) denote hydrogen;

R_(XVIII-7) and R_(XVIII-8) are identical or different and denotephenyl, naphthyl, benzothiazolyl, quinolinyl, pyrimidyl or pyridyl withup to four identical or different substituents in the form of halogen,trifluoromethyl, nitro, cyano, trifluoromethoxy, —SO₂—CH₃ orNR_(XVIII-9)R_(XVIII-10);

R_(XVIII-9) and R_(XVIII-10) are identical or different and denotehydrogen or a straight-chained or branched alkyl of up to three carbonatoms;

E_(XVIII) denotes a cycloalkyl of from three to six carbon atoms or astraight-chained or branched alkyl of up to eight carbon atoms;

R_(XVIII-1) denotes hydroxy;

R_(XVIII-2) denotes hydrogen or methyl;

R_(XVIII-3) and R_(XVIII-4) are identical or different and denotestraight-chained or branched alkyl of up to three carbon atoms; or

R_(XVIII-3) and R_(XVIII-4) taken together form an alkenylene made up ofbetween two and four carbon atoms.

Compounds of Formula XVIII and their methods of manufacture aredisclosed in PCT Publication No. WO 99/15504 and U.S. Pat. No.6,291,477, both of which are incorporated herein by reference in theirentireties for all purposes.

The present invention is particularly useful for acid-sensitive drugswhich chemically react with acidic species, or are otherwise unstable inthe presence of acidic species, including acidic dispersion polymers.Acid-sensitive drugs often have as part of their molecular structurefunctional groups which are reactive under acidic conditions, such assulfonyl ureas, hydroxamic acids, hydroxy amides, carbamates, acetals,hydroxy ureas, esters, and amides. Drugs which include such functionalgroups may be prone to reactions such as hydrolysis, lactonization, ortransesterification in the presence of acidic species.

Acid-sensitive drugs may be identified experimentally by determiningwhether the drug chemically reacts or degrades when dispersed in anacidic polymer. In particular, as used herein, the term “acid-sensitivedrug” refers to a drug which, when dispersed in a “control acidicdispersion,” degrades when stored under controlled aging conditionseither for long storage times at ambient storage conditions or for shortstorage times under elevated temperature and relative humidityconditions. The “control acidic dispersion” used to determine whether adrug is acid-sensitive is a dispersion of the drug and an unneutralizedacidic polymer as described below.

Alternatively, another test to determine whether a drug is anacid-sensitive drug as used herein is to administer the drug to anacidic aqueous solution and plot drug purity or potency versus time. Theacidic solution should have a pH of from 14. Drugs which are acidsensitive are those for which the drug degrades (as evidenced by adecrease in drug purity or potency) by at least 1% within 24 hours ofadministration of the drug to the acidic solution. If the drug degradesby 1% in the 6-24 hour time period, then the drug is “slightlyacid-sensitive.” If the drug degrades by 1% in the 1 hour time period,then the drug is “moderately acid-sensitive.” If the drug degrades by 1%in less than 1 hour, then the drug is “highly acid-sensitive.” Thepresent invention finds particular utility for drugs which are slightlyacid-sensitive, moderately acid-sensitive and highly acid-sensitive.

Examples of acid-sensitive drugs include(+)-N-{3-[3-(4-fluorophenoxy)phenyl]-2-cyclopenten-1-yl}-N-hydroxyurea;omeprazole; etoposide; famotidine; erythromycin; quinapril;lansoprazole; progabide; as well as CCR1 inhibitors such asquinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl-2(S),7-dihydroxy-7-methyl-octyl]amideand quinoxaline-2-carboxylic acid[1-benzyl-4-(4,4-difluoro-1-hydroxy-cyclohexyl)-2-hydroxy-4-hydroxycarbamoyl-butyl]-amide.

The invention is useful for improving the intrinsic dissolution rate ofcompounds selected from the following. The intrinsic dissolution rate isdefined as the rate of dissolution of a pure pharmaceutical activeingredient when conditions such as surface area, agitation-stirringspeed, pH and ionic-strength of the dissolution medium are keptconstant. Intrinsic dissolution rate is further defined as beingmeasured in water at 37° C. using a USP II dissolution apparatusequipped with a Wood's apparatus (Wood, J H; Syarto, J E and Letterman,H: J. Pharm. Sci. 54 (1965), 1068) with a stirring speed of 50 rpm. Theintrinsic dissolution rate is defined in terms of mg of drug dissolvedper minute from a unit surface area, therefore, the intrinsicdissolution rate is referred to in units of mg/min·cm².

The compositions and methods of the invention are particularly usefulfor compounds with an intrinsic dissolution rate of preferably less than0.1 mg/min·cm² and more preferably with less than 0.05 mg/min cm².

Turning now to the chemical structures of specific CCR1 inhibitors, oneclass of CCR1 inhibitors that finds utility with the present inventionconsists of dihydroxyhexanoic acid derivatives having the Formula CCR1-I

wherein R₁ is (C₂-C₉)heteroaryl optionally substituted with one, two orthree substituents independently selected from the group consisting ofhydrogen, halo, cyano, (C₁-C₆)alkyl optionally substituted with one, twoor three fluorine atoms, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₅)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R₂ is phenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—,(C₃-C₁₀)cycloalkyl-(CH₂)_(m)—, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl-(CH₂)_(m)—, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl moieties of saidphenyl-(CH₂)_(m)—, naphthyl-(CH₂)_(m)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(m)— or(C₂-C₉)heteroaryl-(CH₂)_(m)— groups may optionally be substituted withone, two, or three substituents independently selected from the groupconsisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)-[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,phenoxy, benzyloxy, (C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and(C₂-C₉)heteroaryl;

wherein R³ is hydrogen, (C₁-C₁₀)alkyl, (C₃-C₁₀)cycloalkyl-(CH₂)_(n)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(n)—, (C₂-C₉)heteroaryl-(CH₂)_(n)— oraryl-(CH₂)_(n)—; wherein n is an interger from zero to six;

wherein said R₃ (C₁-C₁₀)alkyl group may optionally be substituted withone or more substituents, (preferably from one to three substituents)independently selected from hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; andwherein any of the carbon-carbon single bonds of said (C₁-C₁₀)alkyl mayoptionally be replaced by a carbon-carbon double bond;

wherein the (C₃-C₁₀)cycloalkyl moiety of saidR₃(C₃-C₁₀)cycloalkyl-(CH₂)_(n)— group may optionally be substituted byone to three substitutents independently selected from the groupconsisting of hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein the (C₂-C₉)heterocycloalkyl moiety of said R₃(C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur,oxygen, >S(═O), >SO₂ or >NR⁶, wherein said (C₂-C₉)heterocycloalkylmoiety of said (C₂-C₉)heterocycloalkyl-(CH₂)_(n)— group may optionallybe substituted on any of the ring carbon atoms capable of forming anadditional bond (preferably one to three substitutents per ring) with asubstituent independently selected from the group consisting ofhydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C), H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₈)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein the (C₂-C₉)heteroaryl moiety of said R³(C₂-C₉)heteroaryl-(CH₂)_(n)— group may contain from one to threeheteroatoms independently selected from nitrogen, sulfur or oxygen,wherein said (C₂-C₉)heteroaryl moiety of said(C₂-C₉)heteroaryl-(CH₂)_(n)— group may optionally be substituted on anyof the ring carbon atoms capable of forming an additional bond(preferably one to three substitutents per ring) with a substituentselected from the group consisting of hydrogen, halo, CN, (C₁-C₆)alkyl,hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl; and

wherein said aryl moiety of said R₃ aryl-(CH₂)_(n)— group is optionallysubstituted phenyl or naphthyl, wherein said phenyl and naphthyl mayoptionally be substituted with from one to three substituentsindependently selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkyl HN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

or R₃ and the carbon to which it is attached form a five to sevenmembered carbocyclic ring, wherein any of the carbon atoms of said fivemembered carbocyclic ring may optionally be substituted with asubstituent selected from the group consisting of hydrogen, halo, CN,(C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;wherein one of the carbon-carbon bonds of said five to seven memberedcarbocyclic ring may optionally be fused to an optionally substitutedphenyl ring, wherein said substitutents may be independently selectedfrom hydrogen, halo, CN, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl, HO—(C═O)—,(C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R₄ is hydrogen, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkoxy(C═O)—, (C₃-C₁₀)cycloalkyl-(CH₂)_(q)—,(C₂-C₉)heterocycloalkyl-(CH₂)_(q)—, (C₂-C₉)heteroaryl-(CH₂)_(q)—,phenyl-(CH₂)_(q)—, or naphthyl-(CH₂)_(q)—; wherein said(C₂-C₉)heterocycloalkyl, (C₂-C₉)heteroaryl, phenyl and naphthyl groupsmay be optionally substituted with one or two substituents from thegroup consisting of hydrogen, halo, cyano, (C₁-C₆)alkyl, hydroxy,hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)alkoxy(C₁-C₆)alkyl,HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—, HO—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-(C═O)—O—,(C₁-C₆)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—, H(O═C)—(C₁-C₆)alkyl,(C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl, NO₂, amino,(C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O), (C₁-C₆)alkyl-NH—(C═O)—, [(C₁-C₆)alkyl)₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R₅ is hydrogen, (C₁-C₆)alkyl or amino; or R₄ and R₅ togetherwith the nitrogen atom to which they are attached form a(C₂-C₉)heterocycloalkyl group optionally substituted with one or twosubstituents selected from the group consisting of hydrogen, halo,cyano, (C₁-C₆)alkyl, hydroxy, hydroxy-(C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₅)alkoxy(C₁-C₆)alkyl, HO—(C═O)—, (C₁-C₆)alkyl-O—(C═O)—,HO—(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-O—(C═O)—(C₁-C₆)alkyl,(C₁-C₆)alkyl-(C═O)—O—, (C₁-C₅)alkyl-(C═O)—O—(C₁-C₆)alkyl, H(O═C)—,H(O═C)—(C₁-C₆)alkyl, (C₁-C₆)alkyl(O═C)—, (C₁-C₆)alkyl(O═C)—(C₁-C₆)alkyl,NO₂, amino, (C₁-C₆)alkylamino, [(C₁-C₆)alkyl]₂ amino, amino(C₁-C₆)alkyl,(C₁-C₆)alkylamino(C₁-C₆)alkyl, [(C₁-C₆)alkyl]₂amino(C₁-C₆)alkyl,H₂N—(C═O)—, (C₁-C₆)alkyl-NH—(C═O), [(C₁-C₆)alkyl]₂N—(C═O)—,H₂N(C═O)—(C₁-C₆)alkyl, (C₁-C₆)alkyl-HN(C═O)—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—(C═O)—(C₁-C₆)alkyl, H(O═C)—NH—, (C₁-C₆)alkyl(C═O)—NH,(C₁-C₆)alkyl(C═O)—[NH](C₁-C₆)alkyl,(C₁-C₆)alkyl(C═O)—[N(C₁-C₆)alkyl](C₁-C₆)alkyl, (C₁-C₆)alkyl-S—,(C₁-C₆)alkyl-(S═O)—, (C₁-C₆)alkyl-SO₂—, (C₁-C₆)alkyl-SO₂—NH—, H₂N—SO₂—,H₂N—SO₂—(C₁-C₆)alkyl, (C₁-C₆)alkylHN—SO₂—(C₁-C₆)alkyl,[(C₁-C₆)alkyl]₂N—SO₂—(C₁-C₆)alkyl, CF₃SO₃—, (C₁-C₆)alkyl-SO₃—, phenyl,(C₃-C₁₀)cycloalkyl, (C₂-C₉)heterocycloalkyl, and (C₂-C₉)heteroaryl;

wherein R⁶ is hydrogen, (C₁-C₈)alkyl, (C₁-C₆)alkoxy-(CH₂)_(g)—,(C₁-C₆)alkoxy(C═O)—(CH₂)_(g)—, (C₁-C₆)alkyl-(SO₂)—(CH₂)_(g)—,(C₆-C₁₀)aryloxy-(CH₂)_(g)—, (C₆-C₁₀)aryloxy(C═O)—(CH₂)_(g)—, or(C₆-C₁₀)aryl-(SO₂)—(CH₂)_(g)—;

wherein g is an integer from zero to four;

wherein m is an integer from zero to four;

wherein n is an interger from zero to six;

with the proviso that when one of R⁴ or R⁵ is hydrogen, and the other ofR⁴ or R⁵ is (C₁-C₆)alkyl; R² is (C₃-C₁₀)cycloalkyl or isopropyl and R³is (C₃-C₅)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl,hydroxy(C₁-C₃)alkyl or amino(C₁-C₄)alkyl then R¹ must be other thanindol-5-yl, 6-azaindol-2-yl, 2,3-dichloro-pyrrol-5-yl,4-hydroxyquinolin-3-yl, 2-hydroxyquinoxalin-3-yl, 6-azaindolin-3-yl, oroptionally substituted indol-2 or 3-yl; and the pharmaceuticallyacceptable salts of such compounds.

Unless otherwise indicated, the alkyl and alkenyl groups referred toherein, as well as the alkyl moieties of other groups referred to herein(e.g., alkoxy), may be linear or branched, and they may also be cyclic(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl)or be linear or branched and contain cyclic moieties. Such alkyl andalkoxy groups may be substituted with one, two or three halogen and/orhydroxy atoms, preferably fluorine atoms.

Unless otherwise indicated, “halogen” includes fluorine, chlorine,bromine, and iodine.

“(C₃-C₁₀)cycloalkyl” when used herein refers to cycloalkyl groupscontaining zero to two levels of unsaturation such as cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane,norbornanyl, and the like.

“(C₂-C₉)heterocycloalkyl” when used herein refers to pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl,thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl,isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,tetrahydroazepinyl, piperazinyl, chromanyl, and the like. One ofordinary skill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon or a sp³ hybridizednitrogen heteroatom.

“(C₂-C₉)heteroaryl” when used herein refers to furyl, thienyl,thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl,triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl,pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl,6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl,isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl,indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl,quinoxalinyl, quinazolinyl, benzoxazinyl, and the like. One of ordinaryskill in the art will understand that the connection of said(C₂-C₉)heterocycloalkyl rings is through a carbon atom or a sp³hybridized nitrogen heteroatom.

“Aryl” when used herein refers to phenyl or naphthyl.

“Protected amine” and “protected amino” refers to an amine group withone of the hydrogen atoms replaced with a protecting group (P). Anysuitable protecting group may be used for amine protection. Suitableprotecting groups include carbobenzyloxy, t-butoxy carbonyl (BOC) or9-fluorenyl-methylenoxy carbonyl.

Compounds of Formula CCR1-I and their methods of manufacture aredisclosed in commonly assigned U.S. patent application Ser. No.09/380,269, filed Feb. 5, 1998, U.S. patent application Ser. No.09/403,218, filed Jan. 18, 1999, PCT Publication No. WO98/38167, and PCTPublication No. WO99/40061, all of which are incorporated herein byreference in their entireties for all purposes.

In a preferred embodiment, the CCR1 inhibitor is selected from one ofthe following compounds of Formula CCR1-I:

-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-1(S)-(3-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;-   7,8-difluoro-quinoline-3-carboxylic acid    (1S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;-   6,7,8-trifluoro-quinoline-3-carboxylic acid    (1(S)-benzyl-4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-octyl)-amide;-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-1(S)-(3-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    (1(S)-benzyl-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl)-amide;-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-1(S)-(2-chloro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    [1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-1(S)-(2-fluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid [1    (S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-4(R)-hydroxycarbamoyl-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-1(S)-(3,4-difluoro-benzyl)-2(S),7-dihydroxy-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    (4(R)-carbamoyl-2(S),7-dihydroxy-7-methyl-1(S)-naphthalen-1-ylmethyl-octyl)-amide;-   7,8-difluoro-quinoline-3-carboxylic acid 1    (S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;-   8-fluoro-quinoline-3-carboxylic acid    1(S)-benzyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-7-fluoro-1-(3(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    [4(R)-carbamoyl-1-(2(S)-fluoro-benzyl)-2(S)-hydroxy-7-methyl-octyl]-amide;-   quinoxaline-2-carboxylic acid    [1(S)-benzyl-4(S)-carbamoyl-4(S)-(2,6-dimethyl-tetrahydro-pyran-4-yl)-2(S)-hydroxy-butyl]-amide;-   quinoxaline-2-carboxylic acid    1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;-   quinoxaline-2-carboxylic acid 1    (S)-benzyl-5-cyclohexyl-2(S)-hydroxy-4(R)-methylcarbamoyl-pentyl)-amide;-   quinoxaline-2-carboxylic acid 1    (S)-cyclohexylmethyl-2(S)-hydroxy-7-methyl-4(R)-methylcarbamoyl-octyl)-amide;-   quinoxaline-2-carboxylic acid    [1(S)-benzyl-2(S)-hydroxy-4(S)-hydroxycarbamoyl-4-(1-hydroxy-4-methyl-cyclohexyl)-butyl]-amide;-   quinoxaline-2-carboxylic acid    [1(S)-benzyl-4(S)-(4,4-difluoro-1-hydroxy-cyclohexyl)-2(S)-hydroxy-4-hydroxycarbamoyl-butyl]-amide;-   quinoxaline-2-carboxylic acid    [1(S)-benzyl-4(S)-carbamoyl-4(S)-(4,4-difluoro-cyclohexyl)-2(S)-hydroxy-butyl]-amide;-   quinoline-3-carboxylic acid (1    (S)-benzyl-4(S)-carbamoyl-4-cyclohexyl-2(S)-hydroxy-butyl)-amide;-   quinoxaline-2-carboxylic acid    (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiophen-2-ylmethyl-octyl)-amide;-   quinoxaline-2-carboxylic acid    1(S)-benzyl-4(R)-carbamoyl-7-chloro-2(S)-hydroxy-oct-6-enyl)-amide;-   quinoxaline-2-carboxylic acid    1(S)-benzyl-4(R)-carbamoyl-2(S)-hydroxy-5-phenyl-pentyl)-amide;-   N-1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-5,6-dichloro-nicotinamide;-   quinoxaline-2-carboxylic acid    (4(R)-carbamoyl-2(S)-hydroxy-7-methyl-1(S)-thiazol-4(R)-ylmethyl-octyl)-amide;-   benzothiazole-2-carboxylic acid    1(S)-benzyl-4(R)-carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide;    and-   benzofuran-2-carboxylic acid    1(S)-benzyl-4(R)carbamoyl-7-fluoro-2(S)-hydroxy-7-methyl-octyl)-amide.

In another preferred embodiment, the CCR1 compound has a formula Ia-1:

wherein the substituents are as defined above.

In a preferred method of making the compound Ia-1, the reaction isstarted with Scheme 1. In the herein described processes, thesubstituents are as defined for CCR1-I, and the following:

R₇ is hydroxy, (C₁-C₆)alkyl, or phenyl wherein the phenyl groupunsubstituted or substituted with one, two, or three (C₁-C₆)alkyl,hydroxy, or halogen groups;

R₈ is hydroxy or halogen;

R₉ is phenyl, naphthyl, (C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl or(C₂-C₉)heteroaryl, wherein each of said phenyl, naphthyl,(C₃-C₁₀)cycloalkyl or (C₂-C₉)heteroaryl groups may be unsubstituted orsubstituted with one, two, or three substituents independently selectedfrom the group consisting of halogen, cyano, and (C₁-C₆)alkyl;

P is a protecting group;

X is hydroxy or halogen; and

q is 0, 1, 2, 3, or 4.

In scheme 1 step 1, a compound of the formula (VI-1) is reduced with areducing agent under heat to form a compound of the formula (VId-1). Inone embodiment, the reducing agent is aluminum triisopropoxide andisopropanol. Preferably, the temperature is maintained above roomtemperature, more preferably between about 60° C. and about 82° C. Theproduct alcohol can be isolated by either cooling the reaction mixtureto room temperature, diluting with more isopropanol and collecting thecrystalline material or by cooling the reaction to room temperature andadding 1 N HCL and water and collecting the crystalline material.

Step 2 of scheme 1 includes reacting a compound of the formula R₇—SO₂—Xand a compound of the formula (VId-1) in the presence of a base to formthe compound of the formula (VIe-1). Any amine base is suitable,including pyridine, triethylamine, N-methylmayholine, anddiisoyropylethylamine. In one embodiment, R₇—SO2-R₈ is p-toluenesulfonicacid, methanesulfonic acid, sulfuric acid, or methanesulfonyl chloride.In another embodiment, the conversion of hydroxy dioxane (VId-1) todioxane oxazolidinone (VIe-1) can be achieved by treatment of thehydroxy dioxane (VId-1) with methanesulfonyl chloride and triethylaminein tetrahydrofuran solution and heating the mixture to cause thecyclization of the mesylate formed in situ to the oxazolidinone.

In step 3 of scheme 1, a compound of the formula (VIf-1) may be formedby heating the compound of the formula (VIe-1). The reaction may proceedby dissolving compound VIe-1 in a solvent such as pyridine or N-methylimidazole and heating the mixture for several hours at temperature fromabout 50° C. to about 100° C.; preferably at about 80° C. The mesylate(VIf-1) may be recovered by extraction into an organic solvent such asethyl acetate and removal of the amine solvents by extraction of thesolution with aqueous acid.

Step 4 of scheme 1 depicts reacting hydroxylamine hydrochloride, acompound of the formula R₇—SO₂—X, and a compound of the formula (VIf-1)to form a compound of the formula (VIg-1). In one embodiment, R₇—SO2-Xis p-toluenesulfonic acid, methanesulfonic acid, sulfuric acid, ormethanesulfonyl chloride. The reaction may occur in a solvent, such asmethanol. In one embodiment, the reaction occurs in methanol with tosicacid at reflux for 8 to 24 hours. The resulting nitrile oxazolidinonecontains a small amount of the corresponding ethyl ester which is notremoved since it also is converted to the desired lactone in subsequentsteps.

Step 5 of scheme 1 includes a) hydrolyzing a compound of the formula(VIg-1) with an aqueous solution in the presence of a base, b)protecting the amine group of the compound so formed, and c) cyclizingthe compound so formed with heat and an acid catalyst. In oneembodiment, the compound VIg-1 is hydrolyzed with sodium hydroxide. ThepH is adjusted to approximately 10 and tetrahydrofuran and BOCdicarbonate are added. This provides the protected hydroxy acid, whichmay be heated in 10% acetic acid and toluene to provide the protectedamine lactone (V-1).

The compound of formula (V-1) may also be produced according to scheme2.

In step 1 of scheme 2, a compound of the formula (VI-1) may be reactedwith ozone to for a compound of the formula (VIa-1). The compound VI-1may be present in a solvent, such as ethyl acetate, and the ozoneintroduced through sparging at a temperature below room temperature,preferably at about −15° C., until the starting dioxane ketone issubstantially reacted. Any excess ozone may be removed by bubblingnitrogen through the solution. The resulting crude ketone ester mixturemay be isolated after treatment with aqueous sodium bisulfite to removeany hydroperoxides.

Alternatively, in step 1 of scheme 2, the compound of the formula(VIa-1) may be formed by reacting hypochlorous acid and a compound ofthe formula (VI-1). Such an oxidation reaction typically produceschlorinated forms of the compound VIa-1 as side products in addition othe compound VIa-1. This oxidation reaction proceeds by mixing thecompound VI-1 in solvent, such as acetic acid and/or acetone, and addingsodium hypochlorite, while keeping the mixture at a low temperature,preferably at or below about 0° C.

As a means to convert the side product chlorinated forms of the compoundVIa-1 to compounds of the formula V-1, the compounds formed from thehypochlorous acid oxidation reaction may optionally be hydrogenated byreaction with hydrogen in the presence of a catalyst. The hydrogenationmay include introducing the products from the hypochlorous acidoxidation reaction into a solvent system of tetrahydrofuran and water,followed by addition of a Pd/C catalyst. The resulting mixture issubjected to hydrogen above atmospheric pressure and temperature. In oneembodiment, the pressure is about 80 pounds per square inch and thetemperature is maintained from about 60° C. to about 70° C. until thereaction is substantially complete.

In step 2 of scheme 2, the compound of the formula (VIb-1) may be formedby reacting a silyating agent and a compound of the formula (VIa-1) andreacting the compound so formed with a reducing agent. In oneembodiment, the reducing agent is N-selectride. In another embodiment,the silyating agent is 1,1,1,3,3,3-hexamethyl-disilazane. The reductionreaction may occur at temperatures below about 0° C., preferably belowabout −20° C., more preferably below about −50° C. In addition, thereducing agent may be present in slight excess.

In step 3 of scheme 2, the compound of the formula (V-1) is formed byheating a compound of the formula (VIb-1) in the presence of an acidcatalyst, such as acetic acid. In one embodiment, the cyclizationreaction occurs by introducing the compound VIb-1 into a solventmixture, such as toluene and 10% acetic acid, at the solvent refluxtemperature for 8 to 16 hours. This provides the desired lactone as acrystalline solid after work up.

One method of making the compound of the formula (VI-1) is by reacting acompound of the formula (VII-1)

with a Grinard reagent formed in situ by addition of2-(2-bromo-ethyl)-[1,3]dioxane to a mixture comprising magnesium and thecompound of the formula (VII-1). In one embodiment, the mixture furthercomprises methyl magnesium chloride and/or methyl magnesium bromide in asolvent. Any exotherm formed from the reaction may be controlled by therate of addition of the bromide. The compound of the formula (VII-1) maybe formed by coupling N,O-dimethylhydroxylamine hydrochloride and acompound of the formula (VIII-1)

This coupling reaction may be performed by mixed anhydride procedure. Inone mixed anhydride procedure, compound VIII-1 is combined withmethylene chloride and N-methylmorpholine is added followed by isobutylchloroformate. In a separate mixture, a slurry ofN,O-dimethylhydroxylamine hydrochloride is treated withN-methylmorpholine. The two reaction mixtures are combined and thenquenched with a solution of citric acid in water. This procedurepreferably operates at a temperature below about 20° C., more preferablybelow about 0° C.

Compounds of formula (V-1) may be used to produce compounds of theformula (IVa1-1) according to scheme 3:

In step 1 of scheme 3, the compound of the formula (IVa1-1) may beformed by reacting 4-halo-2-methyl-2-butene and a compound of theformula (V-1) in the presence of a base. Exemplary bases include lithiumdialkyl amides such as lithium N-isopropyl-N-cyclohexylamide, lithiumbis(trimethylsilyl)amide, lithium di-isopropylamide, and potassiumhydride. Suitable solvents include aprotic polar solvents such as ethers(such as tetrahydrofuran, glyme or dioxane), benzene, or toluene,preferably tetrahydrofuran. The aforesaid reaction is conducted at atemperature from about −78° C. to about 0° C., preferably at about −78°C. In one embodiment, alkylation of the lactone (V-1) is accomplished byreacting the lactone (V-1) with lithium bis(trimethylsilyl)amide anddimethylallyl bromide in tetrahydrofuran at a temperature from about−78° C. to about −50° C. Reaction times range from several hours or ifan additive such as dimethyl imidazolidinone is present, the reactionmay be complete in minutes.

Compounds of formula (IVa1-1) may be used to produce compounds of theformula (Ia-1) according to scheme 4:

In step 1 of scheme 4, a compound of the formula (IIIa1-1) is formed byreacting a compound of the formula (IVa1-1) with phosphoric acid.Preferably, this reaction occurs in any suitable solvent, such asnon-alcoholic solvents. Two preferred solvents include tetrahydrofuranand dichloroethane. The reaction may take place at any suitabletemperature, preferably from about −25° C. to about 120° C., morepreferably from about 15° C. to about 40° C. Reaction time is dependenton temperature and batch size, amount other factors, but typicallyreaction time is from about 2 hours to about 14 hours.

Step 2 of scheme 4 depicts coupling a compound IIIa1-1 with a compoundhaving the formula R₁—CO—X to form a compound having the formula(IIa1-1). This coupling reaction is generally conducted at a temperaturefrom about −30° C. to about 80° C., preferably from about 0° C. to about25° C. The coupling reaction may occur with a coupling reagent thatactivates the acid functionality. Exemplary coupling reagents includedicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HBT),N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI), and diethylphosphorylcyanide. The coupling isconducted in an inert solvent, preferably an aprotic solvent, such astetrahydrofuran, acetonitirile, dichloromethane, chloroform, orN,N-dimethylformamide. One preferred solvent is tetrahydrofuran. In oneembodiment, quinoxaline acid is combined with CDI in anhydroustetrahydrofuran and heated to provide the acyl imidazole. CompoundIIIa1-1 is added to the acyl imidazole at room temperature to form thecompound IIa1-1.

Step 3 of scheme 4 includes reacting the compound of formula IIa1-1 withan amine having a formula NHR₄R₅ to form a compound of the formula(Ia-1). In one embodiment, the amine is ammonia either anhydrous in anorganic solvent or as an aqueous solution of ammonium hydroxide added toa polar solvent at a temperature from about −10° C. to about 35° C.,preferably at about 30° C. Suitable solvents include, alcohols, such asmethanol, ethanol, or butanols; ethers such as tetrahydrofuran, glyme ordioxane; or a mixture thereof, including aqueous mixtures. Preferablythe solvent is methanol. In one embodiment, the compound IIa1-1 isdissolved in methanol which has been saturated with ammonia gas. Inanother embodiment, the compound IIa1-1 in methanol is treated withammonium hydroxide in tetrahydrofuran at room temperature.

Scheme 5 represents an alternative method to form compounds of formulaIa-1 from compounds of formula IVa1-1.

In step 1 of scheme 5, a compound of the formula (IVa1-1) is reactedwith a compound of the formula R₉—SO₂—X to form a compound of theformula (IVa2-1). Any suitable acidic deprotection reaction may beperformed. In one example, an excess of p-toluenesulfonic acid hydratein ethyl acetate is introduced to the compound IVa1-1 at roomtemperature. Suitable solvents include ethyl acetate, alcohols,tetrahydrofuran, and mixtures thereof. The reaction may proceed atambient or elevated temperatures. Typically, the reaction issubstantially complete within two and twelve hours. The resultingcompound IVa2-1 may be crystallized and separated from the reactionmixture, and may be further purified to remove impurities byrecrystallization from hot ethyl acetate.

In step 2 of scheme 5, the compound IVa2-1 may be coupled with acompound having the formula R₁—CO—X to form a compound of the formula(IIIa2-1). This coupling reaction is generally conducted at atemperature from about −30° C. to about 80° C., preferably from about 0°C. to about 25° C. The coupling reaction may occur with a couplingreagent that activates the acid functionality. Exemplary couplingreagents include dicyclohexylcarbodiimide/hydroxybenzotriazole(DCC/HBT), N-3-dimethylaminopropyl-N′-ethylcarbodiimide (EDC/HBT),2-ethyoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI)/dimethylaminopyridine (DMAP), anddiethylphosphorylcyanide. The coupling is conducted in an inert solvent,preferably an aprotic solvent, such as acetonitirile, dichloromethane,chloroform, or N,N-dimethylformamide. One preferred solvent is methylenechloride. In one embodiment, quinoxaline acid is combined with methylenechloride, oxalyl chloride and a catalytic amount ofN,N-dimethylformamide to form an acid chloride complex. The compoundIVa2-1 is added to the acid chloride complex followed by triethylamineat a temperature from about 0° C. to about 25° C. to form the compoundIIIa2-1.

Step 3 of scheme 5 includes reacting a compound IIa2-1 withtrifluoroacetic acid to produce a compound of the formula (IIa2-1). Inone embodiment, the hydration with trifluoroacetic acid occurs inmethylene chloride solution at room temperature. The hydration may takeseveral hours to complete at room temperature. A catalytic amount ofsulfuric acid can be added to the reaction solution to increase the rateof reaction.

Step 4 of scheme 5 includes reacting the compound of formula IIa2-1 withan amine having a formula NHR₄R₅ to form a compound of the formula(Ia-1). In one embodiment, the amine is ammonia either anhydrous in anorganic solvent or as an aqueous solution of ammonium hydroxide added toa polar solvent at a temperature from about −10° C. to about 35° C.,preferably at about 30° C. Suitable solvents include, alcohols, such asmethanol, ethanol, or butanols; ethers such as tetrahydrofuran, glyme ordioxane; or a mixture thereof, including aqueous mixtures. Preferablythe solvent is methanol. In one embodiment, the compound IIa2-1 isdissolved in methanol which has been saturated with ammonia gas. Inanother embodiment, the compound IIa2-1 in methanol is treated withammonium hydroxide in tetrahydrofuran at room temperature.

Neutralized Acidic Polymers

Polymers suitable for use in the compositions of the present inventionshould be pharmaceutically acceptable, and have at least some solubilityin aqueous solution at physiologically relevant pHs (e.g. 1-8). Thepolymer should have an aqueous-solubility of at least 0.1 mg/mL over atleast a portion of the pH range of 1-8. The polymer is“concentration-enhancing” as described in more detail below.

While specific polymers are discussed as being suitable for use in thecompositions of the present invention, blends of such polymers may alsobe suitable. Thus the term “polymer” is intended to include blends ofpolymers in addition to a single species of polymer.

By “acidic polymer” is meant any polymer that possesses a significantnumber of acidic moieties. In general, a significant number of acidicmoieties would be greater than or equal to about 0.1 milliequivalents ofacidic moieties per gram of polymer. “Acidic moieties” include anyfunctional groups that are sufficiently acidic that, in contact with ordissolved in water, can at least partially donate a hydrogen cation towater and thus increase the hydrogen-ion concentration. This definitionincludes any functional group or “substituent,” as it is termed when thefunctional group is covalently attached to a polymer, that has a pK_(a)of less than about 10. Here, the term pK_(a) is used in its traditionalform, the pK_(a) being the negative logarithm of the acid ionizationconstant. The pK_(a) will be influenced by such factors as solvent,temperature, water content, and ionic strength of the media or matrix inwhich the acid resides. Unless otherwise noted, the pK_(a) is assumed tobe measured in distilled water at 25° C. Since in general, the moreacidic the polymer the more useful the invention, the invention ispreferred for polymers with functional groups with pK_(a)s of less thanabout 7, and even more preferred with pK_(a)s of less than about 6.Exemplary classes of functional groups that are included in the abovedescription include carboxylic acids, thiocarboxylic acids, phosphates,phenolic groups, and sulfonates. Such functional groups may make up theprimary structure of the polymer such as for polyacrylic acid, but moregenerally are covalently attached to the backbone of the parent polymerand thus are termed “substituents.”

By “neutralized acidic polymer” is meant any acidic polymer for which asignificant fraction of the “acidic moieties” or “acidic substituents”have been “neutralized”; that is, exist in their deprotonated form. The“degree of neutralization,” a, of a polymer substituted with monoproticacids (such as carboxylic acids) is defined as the fraction of theacidic moieties on the polymer that have been neutralized; that is,deprotonated by a base. The degree to which the acidic moieties on thepolymer are neutralized by the base is dependent on (1) the ratio of thenumber of milliequivalents of base per gram of polymer divided by thenumber of milliequivalents of acidic moieties per gram of polymer and(2) the relative pK_(a)s of the base and the acidic polymer. When thepK_(a) of the base is much higher than the pK_(a) of the acidic moietiesof the acidic polymer (that is, the ratio of the pK_(a) of the base tothe pK_(a) of the polymer ≧2), then each milliequivalent of base willapproximately neutralize one milliequivalent of acid. Thus, if 0.5milliequivalent of a strong base per gram of polymer is added to anacidic polymer with 1.0 milliequivalents of acidic moieties per gram ofpolymer, then the degree of neutralization is roughly equal to 0.5.

If a relatively weak base with a pK_(a) value roughly equal to that ofthe polymer's acidic moieties is used to neutralize the polymer (e.g.,the base is the sodium salt of an aliphatic carboxylic acid, such assodium propionate, and the acidic groups on the polymer are aliphaticcarboxylic acids, such as succinate), then more base must be added toachieve the same extent of neutralization. Thus, if 1.0 milliequivalentof a base per gram of polymer, with a pK_(a) roughly equal to the pK_(a)of the polymer, is added to an acidic polymer with 1.0 milliequivalentsof acidic moieties per gram of polymer, then the degree ofneutralization is roughly also equal to 0.5.

When the degree of neutralization, α, is less than 0.9, it may beapproximated by the following equation:

$\alpha = {{\frac{E_{base}}{E_{polymer}} \cdot 1} + 10^{\frac{10^{{pKa},{{Base} - {pKa}},{Polymer}}}{\;^{{pKa},{{Base} - {pKa}},{Polymer}}}}}$where E_(base) is the number of milliequivalents of base per gram ofpolymer, E_(polymer) is the number of milliequivalents of acidicmoieties (of the polymer) per gram of polymer, and pK_(a),Base andpK_(a),polymer are the pK_(a) values of the base and polymer,respectively. It should be noted that if the calculated value of a fromthis equation is greater than 1, the degree of neutralization can beconsidered essentially 1, meaning that essentially all of the acidicmoieties on the polymer have been neutralized.

Alternatively, the degree of neutralization may be measuredexperimentally. Although not strictly applicable to organic solutions orsolid dispersions, the Henderson-Hasselbach equation can be used torelate the effective pH of an aqueous solution or a hydrated dispersionto the degree of neutralization. According to this equation theeffective pH of the solution or hydrated dispersion is given as:pH=pK _(a),polymer−log [(1−α)/α]

As yet another alternative, the degree of neutralization may bedetermined experimentally through spectroscopic analysis or thermalmethods such as differential scanning calorimetry (DSC). Using DSC, forexample, conversion of an acidic cellulosic polymer such as HPMCAS tothe sodium or calcium salt form will lead to a measurable increase inthe glass transition temperature (“T_(g)”) of the polymer alone ordrug/polymer dispersion. The change in physical characteristic such asglass transition temperature may be used to determine the degree ofneutralization.

Typically, for an acidic polymer to be considered a “neutralized acidicpolymer,” α must be at least about 0.001 (or 0.1%), preferably about0.01 (1%) and more preferably at least about 0.1 (10%). Such smalldegrees of neutralization may be acceptable because often the effectivepH of the polymer changes dramatically with small increases in thedegree of neutralization. Nonetheless, even greater degrees ofneutralization are even more preferred. Thus, α is preferably at least0.5 (meaning that at least 50% of the acidic moieties have beenneutralized) and is more preferably at least 0.9 (meaning that at least90% of the acidic moieties have been neutralized).

Often the most chemically stable compositions are formed whenapproximately 100% of the acidic groups of the polymer have beenneutralized, that is α is approximately equal to 1.0. In some casesstable dispersions are formed when excess base is present. However, foracid-sensitive drugs that are also base sensitive, it is often preferredfor α to be approximately equal to 1.0, as this minimizes the presenceof both acid and base. An alternate method involves using excess weakbase (pK_(a) of the base being roughly equal to the pK_(a) of thepolymer's acidic moieties) such that α is about 1.0. The advantage ofusing a weak base is that even the presence of excess base does notcause the dispersion to become overly basic.

Yet another alternative method for determining whether a significantfraction of the acidic moieties have been neutralized is, in the case ofa dispersion comprising an acid-sensitive drug, to disperse theacid-sensitive drug in the neutralized acidic polymer and compare thechemical stability of the drug in the dispersion with the chemicalstability of the same drug in a control composition comprised of thesame quantity of drug dispersed in the acidic polymer (unneutralizedform). A significant fraction of the acidic moieties of the acidicpolymer have been neutralized if the acid-sensitive drug degrades moreslowly when dispersed in the neutralized acidic polymer relative to therate it degrades in the control acidic polymer. Thus, only a portion ofthe acidic moieties or acidic substituents may need to be neutralized.Since the effective pH of an acidic polymer is raised significantly byeven a small change in the degree of neutralization, a relatively lowdegree of neutralization may well result in measurable improvements inthe stability of acid-sensitive drugs.

Neutralized acidic polymers may be either cellulosic or non-cellulosic.A preferred class of acidic polymers consists of cellulosic polymerswith at least one ester- and/or ether-linked acidic substituent in whichthe polymer has a degree of substitution of at least 0.02 for the acidicsubstituent. It should be noted that in the polymer nomenclature usedherein, ether-linked substituents are recited prior to “cellulose” asthe moiety attached to the ether group; for example, “ethylbenzoic acidcellulose” has ethoxybenzoic acid substituents that are ether-linked viathe ethoxy group. Analogously, ester-linked substituents are recitedafter “cellulose” as the carboxylate; for example, “cellulose acetatephthalate” has acetate and phthalate moieties ester-linked to thepolymer. Such polymers include at least one acidic substituent, whichmay be either ether-linked or ester-linked. When substituents possessmore than one carboxylic acid group, generally, unless otherwisespecified, one carboxylic acid group is ester linked to a hydroxyl groupon the polymer backbone and the remaining carboxylic acid group orgroups remain as carboxylic acid groups for the “acidic polymer.” Thus,phthalate groups for cellulose acetate phthalate are substantiallyester-linked to the hydroxyl groups of the cellulose via one carboxylategroup while the second carboxylate group for each phthalate remainsunreacted.

It should also be noted that a polymer name such as “cellulose acetatephthalate” refers to any of the family of cellulosic polymers that haveacetate and phthalate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from 0.02 to 2.9 as long as the other criteria of the polymer aremet. More typically, the degree of substitution for each substituent isfrom about 0.1 to 2.0. “Degree of substitution” refers to the averagenumber of the three hydroxyls per saccharide repeat unit on thecellulose chain that have been substituted. For example, if all of thehydroxyls on the cellulose chain have been phthalate substituted, thephthalate degree of substitution is 3. Also included within each polymerfamily type are cellulosic polymers that have additional substituentsadded in relatively small amounts that do not substantially alter theperformance of the polymer.

Exemplary acidic, ether-linked ionizable substituents include:carboxylic acids, such as carboxymethoxy (commonly referred to ascarboxymethyl), carboxyethoxy (commonly referred to as carboxyethyl),carboxypropoxy (commonly referred to as carboxypropyl), andcarboxyphenoxy (commonly referred to as carboxyphenyl), salicylic acid(attached to the cellulosic polymer via the phenolic hydroxyl),alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid,the various isomers of alkoxyphthalic acid such as ethoxyphthalic acidand ethoxyisophthalic acid, the various isomers of alkoxynicotinic acidsuch as ethoxynicotinic acid, and the various isomers of picolinic acidsuch as ethoxypicolinic acid, etc.; thiocarboxylic acids, such asthioacetic acid; substituted phenoxy groups, such as hydroxyphenoxy,etc.; phosphates, such as ethoxy phosphate; and sulfonates, such asethoxy sulphonate.

Exemplary ester-linked ionizable substituents include: carboxylic acids,such as succinate, citrate, phthalate, terephthalate, isophthalate,trimellitate, and the various isomers of pyridinedicarboxylic acid,etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxygroups, such as amino salicylic acid; phosphates, such as acetylphosphate; and sulfonates, such as acetyl sulfonate. Foraromatic-substituted polymers to also have the requisite aqueoussolubility, it is also desirable that sufficient hydrophilic groups suchas hydroxypropyl or carboxylic acid functional groups be attached to thepolymer to render the polymer aqueous soluble at least at pH valueswhere any ionizable groups are ionized. In some cases, the aromaticgroup may itself be ionizable, such as phthalate or trimellitatesubstituents.

Exemplary acidic cellulosic polymers include such polymers ascarboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethylcellulose, cellulose succinate, cellulose acetate succinate,hydroxyethyl cellulose succinate, hydroxyethyl cellulose acetatesuccinate, hydroxyethyl methyl cellulose succinate, hydroxyethyl methylcellulose acetate succinate, hydroxypropyl cellulose succinate,hydroxypropyl cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methyl cellulose succinate,cellulose phthalate, cellulose acetate phthalate, methyl celluloseacetate phthalate, ethyl cellulose acetate phthalate, cellulosepropionate phthalate, hydroxyethyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate,hydroxypropyl cellulose acetate phthalate succinate, hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

Alternatively, the acidic polymer may be non-cellulosic. Exemplaryacidic non-cellulosic polymers include carboxylic acid-functionalizedvinyl polymers, such as the carboxylic acid functionalizedpolymethacrylates and carboxylic acid functionalized polyacrylates suchas the EUDRAGITS® manufactured by Rohm Tech, Inc., of Malden, Mass.; andcarboxylic acid functionalized starches such as starch glycolate.

The neutralized form of these acidic polymers often provide severaladvantages relative to the unneutralized form. First, where thecomposition is a dispersion, the neutralized form of the acidic polymer,i.e., the salt form of the polymer, tends to have a higher glasstransition temperature relative to the acidic form of the polymer. Toobtain the best physical stability, particularly upon storage for longtimes prior to use, it is preferred that the drug remain, to the extentpossible, in the amorphous state. The inventors have found that this isbest achieved when the mobility of the drug in the dispersion polymer isrelatively low. This is generally the case when the glass-transitiontemperature, T_(g), of the amorphous drug/polymer dispersion issubstantially above the storage temperature of the dispersion. Inparticular, it is preferable that the T_(g) of the amorphous state ofthe drug be at least 40° C. and preferably at least 60° C. Where thedrug itself has a relatively low T_(g) (about 70° C. or less), it ispreferred that the dispersion polymer have a T_(g) of at least 40° C.,preferably at least 70° C. and more preferably greater than 100° C.(Unless otherwise specified, as used herein and in the claims, referenceto a glass transition refers to the glass transition temperaturemeasured at 50% relative humidity.) Exemplary high T_(g) polymersinclude neutralized forms of hydroxypropyl methyl cellulose acetatesuccinate, hydroxypropyl methyl cellulose phthalate, cellulose acetatephthalate, cellulose acetate trimellitate, and other cellulosics thathave alkylate or aromatic substituents or both alkylate and aromaticsubstituents.

Increasing the glass transition temperature of the polymer, and hence ofthe dispersion, improves the physical storage stability of thedispersion by decreasing the mobility of drug in the polymer matrix.Thus, dispersions formed from neutralized acidic polymers, which have ahigher T_(g) relative to the unneutralized form, tend to be morephysically stable.

When the neutralized form of the acidic polymer comprises a multivalentcationic species such as Ca²⁺, Mg²⁺, Al³⁺, Fe²⁺, Fe³⁺, or a diamine,such as ethylene diamine, the cationic species may interact with two ormore neutralized acidic moieties on more than one polymer chain,resulting in an ionic crosslink between the polymer chains. An acidicpolymer may be considered “ionically crosslinked” if the number ofmilliequivalents of multivalent cationic species per gram of polymer isat least 5%, preferably at least 10% the number of milliequivalents ofacidic moieties (of the polymer) per gram of polymer. Alternatively, anacidic polymer may be considered “ionically crosslinked” if sufficientmultivalent cationic species are present such that the neutralizedacidic polymer has a higher T_(g) than the same polymer containingessentially no multivalent cationic species. Drug mobility indispersions formed from such ionically crosslinked polymers isparticularly low relative to dispersions formed from the acidic form ofthe same polymers. Such ionically crosslinked polymers may be formed byneutralization of the acidic polymer using any base where the cationiccounterion of the base is divalent. Thus, calcium hydroxide, magnesiumacetate or ethylene diamine may be added to an acidic polymer such ascellulose acetate phthalate or hydroxypropyl methyl cellulose acetatesuccinate to form a neutralized, ionically crosslinked, acidiccellulosic polymer. Low drug mobility in such polymers may be indicatedby high T_(g) values or, more typically, a decrease in the magnitude ofthe heat capacity increase in the vicinity of the T_(g) or, in somecases, the absence of any apparent T_(g) when the dispersion issubjected to differential thermal analysis. Thus, when sufficientcalcium hydroxide is added to HPMCAS such that the degree ofneutralization is near 1, no T_(g) is apparent when the neutralizedpolymer is subjected to differential thermal analysis. In addition, anacid-sensitive drug dispersed in this polymer is more chemically andphysically stable than when it is dispersed in a non-ionicallycrosslinked neutralized acidic polymer.

Second, the neutralized form of the acidic polymer also tends to improveconcentration enhancement relative to the unneutralized acidic form ofthe polymer. The present inventors have found that for neutralizedacidic polymers, such as hydroxypropyl methyl cellulose acetatesuccinate, the neutralized form of the acidic polymer can, for somedrugs, provide superior concentration enhancement. In addition, theneutralized form of the acidic polymers tend to provide more rapiddissolution of the dispersion. Thus, when the dispersion of the drug andpolymer are introduced into the use environment, the dispersiondissolves more rapidly relative to a dispersion of the drug andunneutralized acidic polymer.

Finally, the neutralized form of the acidic polymer tends to be lessreactive than the acidic polymer. Thus, in addition to minimizingreactions of the drug with the polymer, the selection of a neutralizedacidic enteric polymer also minimizes reactions of the polymer withother excipients.

Neutralized enteric polymers are an especially preferred class ofneutralized acidic polymers. First, enteric polymers typically have ahigher T_(g) relative to non-enteric polymers, and those are capable offorming compositions having improved physical stability. Second, entericpolymers often result in greater drug concentration relative tonon-enteric polymers.

By “enteric polymer” is meant a polymer which has an aqueous solubilitythat is higher at neutral pH (pH ≧6.5) than at low pH (pH ≦5.5).Typically, enteric polymers are relatively insoluble at low pH,typically a pH of less than about 5.5, but at least partially soluble ata pH of greater than about 6.5. Exemplary acidic cellulosic entericpolymers have both (1) an acidic substituent such as succinate,phthalate, trimellitate or carboxyalkyl (such as carboxymethyl) and (2)a hydrophobic substituent such as an alkyl or aryl ether (e.g., methylor ethyl) or an alkyl or aryl ester (e.g., acetate, propionate, butyrateor benzoate). This excludes polymers such as carboxymethyl cellulosebecause they do not possess one or more hydrophobic substituents andpolymers such as methyl cellulose because they do not possess one ormore acidic substituents. It should also be noted that for such polymersto have the requisite solubility properties to be “enteric” polymers,the amount or degree of substitution (“d.s.”) of each substituent mustbe at the appropriate level. For example, if the acetate level of apolymer such as HPMCAS is too low (typically a d.s. value of about 0.1or less), then the polymer will be soluble even at low pH. In contrast,if the acetate level is too high (typically a d.s. value of about 0.4 ormore when the succinate level is about 0.1 to 0.4) then the polymer maybe insoluble at even high pH (pH ≧6.5).

Exemplary cellulosic acidic enteric polymers include hydroxypropylmethyl cellulose acetate succinate, hydroxypropyl methyl cellulosesuccinate, hydroxypropyl cellulose acetate succinate, hydroxyethylmethyl cellulose succinate, hydroxyethyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl celluloseacetate succinate, hydroxyethyl methyl cellulose acetate phthalate,carboxymethyl methyl cellulose, carboxymethyl ethyl cellulose, celluloseacetate phthalate, methyl cellulose acetate phthalate, ethyl celluloseacetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, hydroxypropyl methyl celluloseacetate succinate phthalate, hydroxypropyl methyl cellulose succinatephthalate, cellulose propionate phthalate, hydroxypropyl cellulosebutyrate phthalate, cellulose acetate trimellitate, methyl celluloseacetate trimellitate, ethyl cellulose acetate trimellitate,hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetatetrimellitate succinate, cellulose propionate trimellitate, cellulosebutyrate trimellitate, cellulose acetate terephthalate, celluloseacetate isophthalate, cellulose acetate pyridinedicarboxylate, salicylicacid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate,ethylbenzoic acid cellulose acetate, hydroxypropyl ethylbenzoic acidcellulose acetate, ethyl phthalic acid cellulose acetate, ethylnicotinic acid cellulose acetate, and ethyl picolinic acid celluloseacetate.

Another class of acidic enteric polymers suitable for use with thepresent invention comprises ionizable non-cellulosic polymers. Exemplarynon-cellulosic acidic enteric polymers include: carboxylicacid-functionalized vinyl polymers, such as the carboxylic acidfunctionalized polymethacrylates and carboxylic acid functionalizedpolyacrylates such as the EUDRAGITS® manufactured by Rohm Tech Inc., ofMalden, Mass.; and acidic proteins.

Concentration Enhancement

As described above, the neutralized acidic polymers of the presentinvention are also “concentration-enhancing,” meaning that the polymersimprove the concentration of the low-solubility drug in a useenvironment, and thereby preferably improve bioavailability of the drug.A preferred class of concentration-enhancing polymers comprises polymersthat are “amphiphilic” in nature, meaning that the polymer hashydrophobic and hydrophilic portions. The hydrophobic portion maycomprise groups such as aliphatic or aromatic hydrocarbon groups. Thehydrophilic portion may comprise either ionizable or non-ionizablegroups that are capable of hydrogen bonding such as hydroxyls,carboxylic acids, or esters. It is believed that such amphiphilicpolymers act to retard crystallization or precipitation of the drug.Such polymers may thus act to decrease the rate at which the drug fallsfrom the maximum drug concentration (MDC) to the equilibriumconcentration of drug.

The term “concentration-enhancing” means that the polymer is present ina sufficient amount in the composition so as to improve theconcentration of the drug in a use environment relative to a controlcomposition free from the concentration-enhancing polymer. As usedherein, a “use environment” can be either the in vivo environment of theGI tract, subdermal, intranasal, buccal, intrathecal, ocular,intraaural, subcutaneous spaces, vaginal tract, arterial and venousblood vessels, pulmonary tract or intramuscular tissue of an animal,such as a mammal and particularly a human, or the in vitro environmentof a test solution, such as phosphate buffered saline (PSB) or a ModelFasted Duodenal (MFD) solution. Concentration enhancement may bedetermined through either in vitro dissolution tests or through in vivotests. It has been determined that enhanced drug concentration in invitro dissolution tests in Model Fasted Duodenal (MFD) solution orPhosphate Buffered Saline (PBS) is a good indicator of in vivoperformance and bioavailability. An appropriate PBS solution is anaqueous solution comprising 20 mM sodium phosphate (Na₂HPO₄), 47 mMpotassium phosphate (KH₂PO₄), 87 mM NaCl, and 0.2 mM KCl, adjusted to pH6.5 with NaOH. An appropriate MFD solution is the same PBS solutionwherein additionally is present 7.3 mM sodium taurocholic acid and 1.4mM of 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine. In particular, acomposition containing a concentration-enhancing polymer may bedissolution-tested by adding it to MFD or PBS solution and agitating topromote dissolution.

In one aspect of the invention, a composition containing aconcentration-enhancing polymer of the present invention provides an MDCthat is at least 1.25-fold the MDC provided by a control composition. Inother words, if the MDC provided by the control composition is 100μg/mL, then a composition of the present invention containing aconcentration-enhancing polymer provides an MDC of at least 125 μg/mL.More preferably, the MDC of drug achieved with the compositions of thepresent invention are at least 2-fold, even more preferably at least3-fold, and, most preferably at least 10-fold that provided by thecontrol composition.

The control composition is conventionally the undispersed drug alone(e.g., typically, the crystalline drug alone in its mostthermodynamically stable crystalline form, or in cases where acrystalline form of the drug is unknown, the control may be theamorphous drug alone) or the drug plus a weight of inert diluentequivalent to the weight of polymer in the test composition (by inert ismeant not concentration-enhancing). Where the composition is comprisedof a mixture of a dispersion and additional concentration-enhancingpolymer, the control composition is the dispersion alone without anyadditional concentration-enhancing polymer.

Alternatively, the compositions containing concentration-enhancingpolymers of the present invention provide in an aqueous use environmenta concentration versus time Area Under The Curve (AUC), for any periodof at least 90 minutes between the time of introduction into the useenvironment and about 270 minutes following introduction to the useenvironment that is at least 1.25-fold the AUC provided by anappropriate control composition. More preferably, the AUC achieved withthe compositions of the present invention are at least 2-fold and morepreferably at least 3-fold that of a control composition.

Alternatively, the compositions of the present invention containingconcentration-enhancing polymers, when dosed orally to a human or otheranimal, provide an AUC in drug concentration in the blood plasma orserum that is at least 1.25-fold that observed when an appropriatecontrol composition is dosed. Preferably, the blood AUC is at least2-fold, more preferably at least 3-fold, that of an appropriate controlcomposition. Thus, the compositions of the present invention can beevaluated in either an in vitro or in vivo test, or both.

A typical in vitro test to evaluate enhanced drug concentration can beconducted by

(1) administering with agitation a sufficient quantity of testcomposition (e.g., the dispersion of the low-solubility drug andneutralized acidic polymer) in a test medium, such that if all of thedrug dissolved, the theoretical concentration of drug would exceed theequilibrium concentration of the drug by a factor of at least 2; (2)adding an appropriate amount of a control composition to an equivalentamount of test medium; and (3) determining whether the measured MDCand/or AUC of the test composition in the test medium is at least1.25-fold that provided by the control composition. The concentration ofdissolved drug is typically measured as a function of time by samplingthe test medium and plotting drug concentration in the test medium vs.time so that the MDC and/or AUC can be ascertained. In conducting such adissolution test, the amount of test composition used is an amount suchthat if all of the drug dissolved the drug concentration would be atleast 2-fold to 100-fold that of the solubility of the drug. For somedispersions of very low-solubility drug and acidic neutralized polymer,it may be necessary to administer an even greater amount of thedispersion to determine the MDC.

To avoid drug particulates which would give an erroneous determination,the test solution is either filtered or centrifuged. “Dissolved drug” istypically taken as that material that either passes a syringe microfilter or, alternatively, the material that remains in the supernatantfollowing centrifugation. Filtration can be conducted using any filterwith a pore size rating in the 0.2 to 2.0 □g range. In particular, a 13mm, 0.45 μm polyvinylidine difluoride syringe filter sold by ScientificResources under the trademark TITAN® may be used. Centrifugation istypically carried out in a polypropylene microcentrifuge tube bycentrifuging at 13,000 G for 60 seconds. Other similar filtration orcentrifugation methods can be employed and useful results obtained. Forexample, using other types of microfilters may yield values somewhathigher or lower (±10-40%) than that obtained with the filter specifiedabove but will still allow identification of preferred dispersions. Itis recognized that this definition of “dissolved drug” encompasses notonly monomeric solvated drug molecules but also a wide range of speciessuch as polymer/drug assemblies that have micron or submicron dimensionssuch as drug aggregates, aggregates of mixtures of polymer and drug,micelles, polymeric micelles, colloidal particles or nanocrystals,polymer/drug complexes, and other such drug-containing species that arepresent in the filtrate or supernatant in the specified dissolutiontest.

Alternatively, the concentration-enhancing polymer results in improvedbioavailability. Relative bioavailability of the drug in thecompositions of the present invention can be tested in vivo in animalsor humans using conventional methods for making such a determination. Anin vivo test, such as a crossover study, may be used to determinewhether a composition provides an enhanced relative bioavailabilitycompared with a control. In an in vivo crossover study a “testcomposition” of drug and concentration-enhancing polymer is dosed tohalf a group of test subjects and, after an appropriate washout period(e.g., one week) the same subjects are dosed with a “controlcomposition” that comprises an equivalent quantity of drug as the “testcomposition.” The other half of the group is dosed with the controlcomposition first, followed by the test composition. The relativebioavailability is measured as the concentration in the blood (serum orplasma) versus time area under the curve (AUC) determined for the testgroup divided by the AUC in the blood provided by the controlcomposition. Preferably, this test/control ratio is determined for eachsubject, and then the ratios are averaged over all subjects in thestudy. In vivo determinations of AUC can be made by plotting the serumor plasma concentration of drug along the ordinate (y-axis) against timealong the abscissa (x-axis). Generally, the values for AUC represent anumber of values taken from all of the subjects in a patient testpopulation averaged over the entire test population.

A preferred embodiment of the invention is one in which the relativebioavailability of the test composition is at least 1.25 relative to acontrol composition as described above. (That is, the AUC in the bloodprovided by the test composition is at least 1.25-fold the AUC providedby the control composition.) An even more preferred embodiment of theinvention is one in which the relative bioavailability of the testcomposition is at least 2, more preferably at least 3 relative to acontrol composition of the drug but with no polymer present, asdescribed above. The determination of AUCs is a well-known procedure andis described, for example, in Welling, “Pharmacokinetics Processes andMathematics,” ACS Monograph 185 (1986).

Often the enhancement in drug concentration or relative bioavailabilitythat is observed increases as the drug:polymer ratio decreases from avalue of about 1 (50 wt % drug) to a value of about 0.11 (10 wt % drug).The drug:polymer ratio that yields optimum results varies from drug todrug and is best determined in in vitro dissolution tests and/or in vivobioavailability tests. However, the amount of polymer that can be usedin a dosage form is often limited by the total mass requirements of thedosage form. For example, when oral dosing to a human is desired, at lowdrug-to-polymer ratios the total mass of drug and polymer may beunacceptably large for delivery of the desired dose in a single tabletor capsule. Thus, it is often necessary to use drug-to-polymer ratiosthat are less than optimum in specific dosage forms to provide asufficient drug dose in a dosage form that is small enough to be easilydelivered to a use environment.

Improved Chemical Stability

With respect to dispersions comprising an acid-sensitive drug and aneutralized acidic polymer, the resulting compositions provide improvedchemical stability of the drug. That is, the acid-sensitive drug, whendispersed in a neutralized acidic polymer, degrades less over time undercontrolled storage conditions than when dispersed in the unneutralizedacidic polymer.

In general, drug degradation may be measured using any conventionalmethod for measuring the purity or potency of drug in a pharmaceuticalcomposition. For example, the amount of active drug present in adispersion may be initially measured using high-performance liquidchromatography (HPLC) or other analytical techniques well known in theart. Alternatively, the amount of drug initially present may becalculated from the amount of drug present in the dispersionformulation. The potency of the dispersion is then measured afterstorage at controlled temperature and humidity conditions for anappropriate period of time. A decrease in potency indicates that achemical reaction has occurred, leading to a decrease in the amount ofactive drug present in the dispersion, and is an indication of poorchemical stability.

An alternative method used to evaluate chemical stability is to analyzethe rate of increase in the amount of drug degradant(s) in thedispersion, which would indicate reaction of the drug. An HPLC or otheranalytical technique may be used to determine the concentration of drugdegradant(s) in a dispersion. The amount of the degradant(s) is measuredbefore and after storage under controlled storage conditions. The amountof increase in the drug degradant(s) may be used to determine the amountof decrease in percent “purity of the drug.” The “percent drug purity”is defined as 100 times the total amount of drug present divided by thetotal amount of drug initially present. Thus, percent drug purity may becalculated by the formula

${{wt}\mspace{11mu}\%\mspace{14mu}{drug}\mspace{14mu}{purity}} = {\left( \frac{{total}\mspace{14mu}{{amt}.\mspace{14mu}{of}}\mspace{14mu}{drug}\mspace{14mu}{present}}{{total}\mspace{14mu}{{amt}.\mspace{14mu}{of}}\mspace{14mu}{drug}\mspace{14mu}{{init}.\mspace{14mu}{present}}} \right)*100}$

When the drug purity is calculated from the total amount of impurities,“percent drug purity” may be calculated by assuming that the “totalamount of drug initially present,” given in wt %, is equal to 100 wt %minus the wt % of total initial impurities, and that “total amount ofdrug present” is equal to 100 wt % minus the wt % of total impuritiesafter storage, that is, at some later time. This method is equivalent tocalculating “percent drug purity” by the formula:

$\mspace{14mu}{\begin{matrix}{{wt}\mspace{11mu}\%} \\{{drug}\mspace{14mu}{purity}}\end{matrix} = {\left\lbrack {1 - \left( \frac{{Total}\mspace{14mu}{{amt}.\mspace{14mu}{of}}\mspace{14mu}{Impurities}\mspace{20mu}{present}}{{total}\mspace{14mu}{{amt}.\mspace{14mu}{of}}\mspace{14mu}{drug}\mspace{14mu}{{init}.\mspace{14mu}{present}}} \right)} \right\rbrack*100}}$

The rate at which drug degradation occurs is generally dependent on thestorage conditions. The drug, when formulated as a composition of thepresent invention, should be stable at ambient temperature and humidityconditions (e.g., relative humidities of 20% to 60%) for long periods oftime, such as months or years. However, to expedite testing, the storageconditions may employ elevated temperature and/or humidity to simulatelonger storage times at ambient conditions. The storage time may varyfrom a few days to weeks or months, depending on the reactivity of thedrug and the storage conditions.

A “degree of degradation” of drug following storage may be determined bysubtracting the final drug percent purity (either determined bymeasuring the decrease in drug present or an increase in the amount ofdrug degradants present) from the initial percent purity. For example,for a dispersion initially containing 100 mg drug, and no measurableimpurities it would have an initial percent purity of 100 wt %. If,after storage, the amount of drug in the dispersion decreases to 95 mg,the final percent purity would be 95 wt % and the “degree ofdegradation” is 5 wt % (100 wt %-95 wt %). Alternatively, if 100 mg ofdrug substance were found to initially have 1 mg of impurities present,it would have an initial “percent purity” of 99 wt %. If, after storage,the total impurities present had increased to 6 wt %, the final percentpurity would be 94 wt % and the “degree of degradation” would be 5 wt %(99 wt %-94 wt %).

Alternatively, “degree of degradation” can be determined by subtractingthe amount of one or more specific drug degradants initially presentfrom the amount of that specific degradant present after storage. Such ameasure is useful where there are several drug degradants, of which onlyone (or a few) is of concern. The degree of degradation may becalculated on the basis of only those degradants that are of concern,rather than all of the degradants. For example, if a drug initiallycontained a specific degradant at a concentration of 1 wt % and afterstorage the concentration of that degradant was 6 wt %, the degree ofdegradation would be 5 wt % (6 wt %-1 wt %).

The dispersions of the present invention exhibit improved chemicalstability relative to a control composition comprised of an equivalentquantity of acid-sensitive drug dispersed in the unneutralized form ofthe acidic polymer. The “unneutralized form” of the acidic polymer meansthat the degree of neutralization is less than 0.001. For example, wherethe dispersion of the present invention utilizes the sodium salt ofhydroxy propyl methyl cellulose acetate succinate as the neutralizedform of the acidic dispersion polymer, the control composition iscomprised of an equivalent amount of drug dispersed in hydroxypropylmethyl cellulose acetate succinate in which essentially none of thesuccinate groups are neutralized.

A relative degree of improvement in chemical stability may be determinedby taking the ratio of the degree of degradation of the drug in acontrol dispersion and the degree of degradation of the drug in a testdispersion of the present invention under the same storage conditionsfor the same storage time period. The test dispersion is simply thedispersion of acid-sensitive drug, neutralized form of the acidicpolymer, and optional additional excipients of the present invention.The control dispersion is the same as the test dispersion with theexception that the acidic polymer in the unneutralized form replaces theneutralized acidic polymer of the test dispersion. For example, wherethe degree of degradation of a drug in a test dispersion comprised of aneutralized acidic dispersion polymer is 1 wt %, and the degree ofdegradation of the control composition is 50 wt %, the relative degreeof improvement is 50 wt %/1 wt %, or 50. For dispersions ofacid-sensitive drugs and neutralized acidic polymers of the presentinvention, the relative degree of improvement is at least 1.25. When thedrug is particularly acid-sensitive, larger relative degrees ofimprovement may be necessary in order for the chemical stability of thedispersion to be pharmaceutically acceptable. In such cases, theinvention provides greater chemical stability when the relative degreeof improvement is at least about 2, preferably at least about 5, andeven more preferably at least 10. In fact, some dispersions may achievea relative degree of improvement greater than 100.

The particular storage conditions and time of storage may be chosen asconvenient depending on the degree of acid-sensitivity of the drug, theparticular acidic polymer used in the control dispersion, and the ratioof drug to polymer in the dispersion. Where the drug is particularlyacid-sensitive, or where the dispersion has a low ratio of drug topolymer, then shorter storage time periods may be used. Where the rateof drug degradation is linear, the relative degree of improvement willbe independent of the storage time. However, where the rate of drugdegradation is non-linear under controlled storage conditions, thestability test used to compare the test dispersion with the controldispersion is preferably chosen such that the degree of degradation issufficiently large that it may be accurately measured. Typically, thetime period is chosen so as to observe a degree of degradation of atleast 0.1 wt % to 0.2 wt %. However, the time period is not so long thatthe ratio of drug to polymer changes substantially. Typically, the timeperiod is such that the observed degree of degradation for the testcomposition is less than 50 wt % and preferably less than 20 wt %. Whenthe rate of drug degradation in the control composition is relativelyslow, the test is preferably conducted over a long enough period of timeunder controlled storage conditions to allow a meaningful comparison ofthe stability of the test dispersion with the control dispersion.

A stability test which may be used to test whether a dispersion meetsthe chemical stability criteria described above is storage of the testdispersion and the control dispersion for six months at 40° C. and 75%RH. A relative degree of improvement may become apparent within ashorter time, such as three to five days, and shorter storage times maybe used for some acid-sensitive drugs. When comparing dispersions understorage conditions which approximate ambient conditions, e.g., 25° C.and 60% RH, the storage period may need to be from several months up totwo years.

In addition, it is preferred that the dispersions comprisingacid-sensitive drug and neutralized acidic polymer(s) result in drugstability such that the acid-sensitive drug has a degree of degradationof less than about 2 wt %, more preferably less than about 0.5 wt %, andmost preferably less than about 0.1 wt % when stored at 40° C. and 75%RH for six months, or less than about 2 wt %, more preferably less thanabout 0.5 wt %, and more preferably less than about 0.1 wt %, whenstored at 30° C. and 60% RH for one year, or less than about 2 wt %,more preferably less than about 0.5 wt %, and more preferably less thanabout 0.1 wt %, when stored at ambient conditions for two years.Nevertheless, the compositions of the present invention may have adegree of degradation that is much greater than the preferred values, solong as the dispersion achieves the degree of improvement relative to acontrol composition as described above.

Neutralization Methods

The acidic polymers for use with the compositions of the presentinvention may be neutralized by any conventional method known in the artwhich results in the desired degree of neutralization. In general, theacidic polymer is neutralized through the addition of a sufficientamount of base to a solution or composition containing the polymer. Thepolymer may be neutralized prior to formation of the dispersion. Forexample, a base may be added to a solution of the acidic polymerresulting in neutralization of the polymer's acidic functional groups.Alternatively, the acidic polymer may be neutralized during formation ofthe dispersion, or may be neutralized following formation of thedispersion.

A wide range of bases may be used to neutralize the acidic polymer. Theterm “base” is used broadly to include not only strong bases such assodium hydroxide, but also weak bases and buffers that are capable ofachieving the desired degree of neutralization. Examples of basesinclude hydroxides, such as sodium hydroxide, calcium hydroxide,ammonium hydroxide, choline hydroxide; bicarbonates, such as sodiumbicarbonate, potassium bicarbonate, and ammonium bicarbonate;carbonates, such as ammonium carbonate, and sodium carbonate; amines,such as tris(hydroxymethyl)amino methane, ethanolamine, diethanolamine,N-methyl glucamine, glucosamine, ethylenediamine,N,N′-dibenzylethylenediamine, N-benzyl-2-phenethylamine,cyclohexylamine, cyclopentylamine, diethylamine, isopropylamine,diisopropylamine, dodecylamine, and triethylamine; proteins, such asgelatin; amino acids such as lysine, arginine, guanine, glycine, andadenine; polymeric amines, such as poly amino methacrylates, such asEudragit E; conjugate bases of various acids, such as sodium acetate,sodium benzoate, ammonium acetate, disodium phosphate, trisodiumphosphate, calcium hydrogen phosphate, sodium phenolate, sodium sulfate,ammonium chloride, and ammonium sulfate; salts of EDTA, such as tetrasodium EDTA; and salts of various acidic polymers such as sodium starchglycolate, sodium carboxymethyl cellulose and sodium polyacrylic acid.The use of the bicarbonates is in some cases preferred, as thesegenerate carbon dioxide during the neutralization process, which can beremoved easily following neutralization.

When the drug itself is basic the drug may constitute all or a portionof the base used to neutralize the acidic dispersion polymer. Thus, whenthe drug is the salt of an organic acid or an amine in its free baseform, combination of the drug and the acidic polymer in adispersion-formation process such as spray-drying, melt congealing,screw extrusion or the like may result in a composition of theinvention. This is particularly true when the number of equivalents ofbase added in the form of the drug is equal to half or more of thenumber equivalents of and present as part of the polymer. Additionalbase that is not the drug may optionally be added.

As described previously, dispersions that contain significant quantitiesof a divalent cationic or multivalent cationic species such as Ca²⁺,Mg²⁺, or a diamine such as ethylene diamine are particularly desirableas they may ionically crosslink the dispersion polymer. This mayconveniently be accomplished by adding such species in their basic form.Thus, exemplary bases containing a dicationic species include: calciumhydroxide, calcium acetate, magnesium hydroxide, magnesium stearate,aluminum hydroxide, ethylene diamine, polyamino methyacrylate, or anyother pharmaceutically acceptable compound that may form a dicationic orpolycationic species in the dispersion.

In one neutralization method, the polymer is neutralized prior toformation of the dispersion. The acidic polymer is first dissolved in asuitable solvent prior to addition of the base. Suitable solventsinclude water; ketones, such as acetone; alcohols, such as methanol,ethanol, isopropanol; and other solvents such as tetrahydrofuran,benzene, and dichloromethane. Mixtures of solvents, including mixturesof water and one or more organic solvents, may also be used. Inparticular, when organic solvents are used, addition of at least a smallamount of water is often preferred to facilitate the neutralizationprocess and to minimize excessively high or low pH values. The solventmay be selected such that it is a solvent for the neutralized acidicpolymer but not necessarily a solvent for the acidic polymer prior toneutralization. This may facilitate isolation of the neutralized acidicpolymer. Thus, prior to adding the base, the acidic polymer is notcompletely dissolved in the solvent. As the base is added, theneutralized acidic polymer dissolves.

For example, the acidic polymer HPMCAS may be neutralized by addition ofa base to an aqueous solution containing HPMCAS. HPMCAS has a pK_(a) ofabout 5. One procedure for neutralizing HPMCAS is to suspend the HPMCASin distilled water. A base, such as sodium bicarbonate can then be addedto this solution. As the base is added, the succinate groups on HPMCASare neutralized, forming the sodium salt form of HPMCAS and at the sametime the pH of the solution increases. When the pH of the solutionreaches about 5, the pK_(a) of the acidic moeities (succinate groups) ofthe polymer, the degree of neutralization, α, is 0.5. More base may beadded, increasing the pH of the solution and increasing the extent ofneutralization. Care must be taken, however, not to increase the pH toohigh, as at high pH (greater than about 8), the excess base can lead todegradation of the polymer. In the case of HPMCAS, such degradation cantake the form of hydrolysis of ester-linked groups such as acetate orsuccinate or even cleavage of the cellulosic backbone of the polymer.

Following neutralization, the neutralized acidic polymer may be isolatedand purified using methods known in the art. Examples of suitablemethods include precipitation using a non-solvent, evaporation,rotoevaporation, spray-drying, and lyophilization. The neutralizedacidic polymer can then be used to form the dispersion with the drugusing the methods described below.

In another method, the neutralized acidic polymer is not isolated fromthe solvent, but instead, the drug is added to the polymer/solventsolution and the dispersion formed directly from this mixture. Examplesof processes for forming the dispersion from such a solution aredescribed below in connection with the discussion regarding formation ofdispersions.

Another method for neutralizing the polymer during formation of thedispersion is to use a basic form of a drug which is capable of existingin a less basic form (for example where the drug has two basicsubstituents) or a non-basic form, such as a neutral or acidic form. Thebasic drug itself may be used to neutralize the acidic polymer,resulting in a dispersion of neutralized acidic polymer and drug. Thedrug in the dispersion may be partially or completely converted to itsless basic or non-basic form.

Another method for neutralizing an acidic dispersion polymer is toneutralize the polymer after the dispersion has been formed. In thismethod, a base is blended with the dispersion of the acid-sensitive drugand acidic polymer. Exemplary bases that may be used to neutralize theacidic polymer include any of those listed above for neutralization of apolymer in solution but include, in particular, salts of acidic polymerssuch as sodium starch glycolate, cross carmellose sodium, and sodiumcarboxymethyl cellulose; amine functionalized polymers such asaminomethacryrates, amino acrates, chitin, and proteins; inorganic basessuch as tribasic calcium phosphate, calcium carbonate, disodium hydrogenphosphate and aluminum hydroxide; salts of acidic compounds such asmagnesium stearate, sodium acetate, and potassium lactate; and aminessuch as meglumine and mono-, di- and tri-ethanolamine. Many of thesebases, such as phosphate, carbonate and carboxylate salts, may be addedin excess and as such may act as buffers, maintaining a relativelyneutral pH (e.g., pH between about 5 and 9) in the composition. Theamount of base to be blended with the dispersion should generally be inthe range from about 0.1 to about 2.0 equivalents of base per equivalentof the acidic polymer moieties.

The amount of base to be blended with the dispersion may be determinedby various techniques. For example, various dispersions of drug, acidicpolymer, and base may be made that have varying levels of baseequivalents per acidic polymer equivalent. An improvement in chemicalstability during storage is an indication that sufficient base has beenadded. Alternatively, the polymer and drug may be dissolved or slurriedin water and the pH monitored as base is added. The amount of base peramount of drug and polymer to achieve the desired pH may be noted.Generally, adding sufficient base to substantially increase the pH maybe sufficient. The amount of base required to raise the pH to a valuenear 6 to 8 is often preferred.

The base and dispersion may be blended together to create a physicalmixture using any conventional method known in the art. Thus, the baseand dispersion may be blended together using wet- or dry-granulation. Ahigh degree of blending or mixing is generally preferred in order toachieve maximum neutralization of the acidic polymer using this method.In general, the neutralization is facilitated by the presence ofsolvent, particularly water. For example, simple storage of the blendedcomposition as a bulk material or in the form of a dosage form such as atablet, granule or capsule under humid conditions for a period of a fewhours to 30 days can result in sufficient neutralization of the acidicpolymer dispersion. Likewise, the neutralization process may befacilitated by wet granulation processes in which the blend isrelatively wet during at least a portion of the processing time.

Neutralization may be quantified by numerous methods, including storageand measurement of reduced drug degradation rates, spectroscopicanalysis, potentiometric analysis, and thermal methods such asdifferential scanning calorimetry (DSC). Using DSC, for example,conversion of an acidic cellulosic polymer such as HPMCAS to the sodiumor calcium salt form will lead to a measurable increase in the glasstransition temperature of the polymer alone or drug/polymer dispersion.In the case of adding calcium the glass transition may be completelyabsent from the DSC data.

In addition, when dispersions are made by thermal processes such as amelt-congeal process, or an extrusion process, using, for example, atwin-screw extruder, that may form a dispersion by a combination ofthermal and mechanical means, then the basic excipient may be blendedwith the drug and acidic polymer and the blend then fed to themelt-congeal or extrusion process apparatus. Such processes may alsooptionally include small amounts of solvent. Neutralization may occurcompletely or in part during processing as the heat, mechanical shearand solvent, if present, facilitate the neutralization process.

Preparation of Dispersions

In a preferred aspect of the invention, the mixture of drug andneutralized acidic polymer is a solid dispersion. While the drug in itspure state may be crystalline or amorphous, at least a major portion ofthe drug in the dispersion is amorphous. By “amorphous” is meant simplythat the drug is in a non-crystalline state. As used herein, the term “amajor portion” of the drug means that at least 60% of the drug in thedispersion is in the amorphous form, rather than the crystalline form.In general, drug is more reactive in its amorphous state relative to itscrystalline state and so the need to neutralize the dispersion polymerto prevent degradation of acid-sensitive drug increases as the fractionof drug in the amorphous state increases. It has also been found thatthe aqueous concentration of the drug in a use environment tends toimprove as the amount of amorphous drug present in the dispersionincreases. Preferably, the drug in the dispersion is “substantiallyamorphous.” As used herein, “substantially amorphous” means that theamount of the drug in amorphous form is at least 75%. More preferably,the drug in the dispersion is “almost completely amorphous” meaning thatthe amount of drug in the amorphous form is at least 90%. Amounts ofcrystalline drug may be measured by powder X-ray diffraction, ScanningElectron Microscope (SEM) analysis, differential scanning calorimetry(DSC), or any other standard quantitative measurement.

The amorphous drug can exist as a pure phase, as a solid solution ofdrug homogeneously distributed throughout the polymer or any combinationof these states or those states that lie intermediate between them. Tomaximize the concentration enhancement provided by the dispersion, thedispersion is preferably substantially homogeneous so that the amorphousdrug is dispersed as homogeneously as possible throughout the polymer.As used herein, “substantially homogeneous” means that the drug presentin relatively pure amorphous domains within the solid dispersion isrelatively small, and is less than 20%, and preferably less than 10%, ofthe total amount of drug. While the dispersion may have some drug-richdomains, it is preferred that the dispersion itself have a single glasstransition temperature (T_(g)) which demonstrates that the dispersion issubstantially homogeneous. This contrasts with a simple physical mixtureof pure amorphous drug particles and pure amorphous polymer particleswhich generally display two distinct T_(g)s, one that of the drug andone that of the polymer. T_(g) as used herein is the characteristictemperature where a glassy material, upon gradual heating, undergoes arelatively rapid (e.g., 10 to 100 seconds) physical change from a glassstate to a rubber state. Dispersions of the present invention that aresubstantially homogeneous generally are more physically stable and haveimproved concentration-enhancing properties and, in turn, improvedbioavailability, relative to nonhomogeneous dispersions.

Dispersions of the drug and neutralized acidic polymer may be madeaccording to any known process which results in at least a major portionof the drug in the dispersion being in the amorphous state. Suchprocesses include mechanical, thermal and solvent processes. Exemplarymechanical processes include milling and extrusion; melt processesinclude high temperature fusion, solvent modified fusion andmelt-congeal processes; and solvent processes include non-solventprecipitation, spray coating and spray-drying. See, for example, U.S.Pat. No. 5,456,923, U.S. Pat. No. 5,939,099 and U.S. Pat. No. 4,801,460which describe formation of dispersions via extrusion processes; U.S.Pat. No. 5,340,591 and U.S. Pat. No. 4,673,564 which describe formingdispersions by milling processes; and U.S. Pat. No. 5,684,040, U.S. Pat.No. 4,894,235 and U.S. Pat. No. 5,707,646 which describe the formationof dispersions via melt/congeal processes, the disclosures of which areincorporated by reference.

In particular, when either the neutralized acidic polymer or the drughas a relatively low melting point, typically less than about 200° C.and preferably less than about 160° C., extrusion or melt-congealprocesses that provide heat and/or mechanical energy are often suitablefor forming almost completely amorphous dispersions. Often, when thedrug has significant solubility in the dispersion material, such methodsmay also make substantially homogeneous dispersions. For example, 10 wt% drug and 90 wt % of a suitable polymer may be dry blended, with orwithout the addition of water, and the blend fed to a twin-screwextrusion device. The processing temperature may vary from about 50° C.up to about 200° C. depending on the melting point of the drug andpolymer, which is a function of the polymer grade chosen and the amountof water, if any, added. Generally, the higher the melting point of thedrug and polymer, the higher the processing temperature. Generally, thelowest processing temperature that produces a satisfactory dispersion(almost completely amorphous and substantially homogeneous) is chosen.

A preferred method for forming dispersions is “solvent processing,”which consists of dissolution of the drug and one or more neutralizedacidic polymers in a common solvent. The term “solvent” is used broadlyand includes mixtures of solvents. “Common” here means that the solvent,which can be a mixture of compounds, will simultaneously dissolve thedrug and the polymer(s). For dispersions formed from neutralized acidicpolymers that have not been isolated from the polymer/solvent solutionto which base has been added, the acid-sensitive drug may be added tothe solution containing the solvent and neutralized acidic polymer, andthe dispersion then may be formed directly from the resulting solution.

After both the drug and polymer(s) have been dissolved, the solvent israpidly removed by evaporation or by mixing with a non-solvent.Exemplary processes are spray-drying, spray-coating (pan-coating,fluidized bed coating, etc.), vacuum evaporation, and precipitation byrapid mixing of the polymer and drug solution with CO₂, water, or someother non-solvent. Preferably, removal of the solvent results in a soliddispersion which is substantially homogeneous. In substantiallyhomogeneous dispersions, the drug is dispersed as homogeneously aspossible throughout the polymer and can be thought of as a solidsolution of drug dispersed in the polymer(s). When the resultingdispersion constitutes a solid solution of drug in polymer, thedispersion may be thermodynamically stable, meaning that theconcentration of drug in the polymer is at or below its equilibriumvalue, or it may be considered a supersaturated solid solution where thedrug concentration in the dispersion polymer(s) is above its equilibriumvalue.

The solvent may be removed through the process of spray-drying. The termspray-drying is used conventionally and broadly refers to processesinvolving breaking up liquid mixtures into small droplets (atomization)and rapidly removing solvent from the mixture in a container(spray-drying apparatus) where there is a strong driving force forevaporation of solvent from the droplets. The strong driving force forsolvent evaporation is generally provided by maintaining the partialpressure of solvent in the spray-drying apparatus well below the vaporpressure of the solvent at the temperature of the drying droplets. Thisis accomplished by either (1) maintaining the pressure in thespray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); (2)mixing the liquid droplets with a warm drying gas; or (3) both. Inaddition, at least a portion of the heat required for evaporation ofsolvent may be provided by heating the spray solution.

Solvents suitable for spray-drying can be any organic compound in whichthe drug and polymer are mutually soluble. Preferably, the solvent isalso volatile with a boiling point of 150° C. or less. In addition, thesolvent should have relatively low toxicity and be removed from thedispersion to a level that is acceptable according to The InternationalCommittee on Harmonization (ICH) guidelines. Removal of solvent to thislevel may require a processing step such as tray-drying subsequent tothe spray-drying or spray-coating process. Preferred solvents includealcohols such as methanol, ethanol, n-propanol, iso-propanol, andbutanol; ketones such as acetone, methyl ethyl ketone and methyliso-butyl ketone; esters such as ethyl acetate and propylacetate; andvarious other solvents such as acetonitrile, methylene chloride,toluene, and 1,1,1-trichloroethane. Lower volatility solvents such asdimethyl acetamide or dimethylsulfoxide can also be used. Mixtures ofsolvents, such as 50% methanol and 50% acetone, can also be used, as canmixtures with water as long as the polymer and drug are sufficientlysoluble to make the spray-drying process practicable. As describedpreviously, addition of at least a few percent water is often preferred.

Generally, the temperature and flow rate of the drying gas is chosen sothat the polymer/drug-solution droplets are dry enough by the time theyreach the wall of the apparatus that they are essentially solid, and sothat they form a fine powder and do not stick to the apparatus wall. Theactual length of time to achieve this level of dryness depends on thesize of the droplets. Droplet sizes generally range from 1 μm to 500 μmin diameter, with 5 to 100 μm being more typical. The largesurface-to-volume ratio of the droplets and the large driving force forevaporation of solvent leads to actual drying times of a few seconds orless, and more typically less than 0.1 second. This rapid drying isoften critical to the particles maintaining a uniform, homogeneousdispersion instead of separating into drug-rich and polymer-rich phases.As above, to get large enhancements in concentration and bioavailabilityit is often necessary to obtain as homogeneous of a dispersion aspossible. Solidification times should be less than 100 seconds,preferably less than a few seconds, and more preferably less than 1second. In general, to achieve this rapid solidification of thedrug/polymer solution, it is preferred that the size of droplets formedduring the spray-drying process are less than about 100 μm in diameter.The resultant solid particles thus formed are generally less than about100 μm in diameter.

Following solidification, the solid powder typically stays in thespray-drying chamber for about 5 to 60 seconds, further evaporatingsolvent from the solid powder. The final solvent content of the soliddispersion as it exits the dryer should be low, since this reduces themobility of drug molecules in the dispersion, thereby improving itsstability. Generally, the solvent content of the dispersion as it leavesthe spray-drying chamber should be less than 10 wt % and preferably lessthan 2 wt %. In some cases, it may be preferable to spray a solvent or asolution of a polymer or other excipient into the spray-drying chamberto form granules, so long as the dispersion is not adversely affected.

Spray-drying processes and spray-drying equipment are describedgenerally in Perry's Chemical Engineers' Handbook, Sixth Edition (R. H.Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984,pages 20-54 to 20-57. More details on spray-drying processes andequipment are reviewed by Marshall “Atomization and Spray-Drying,” 50Chem. Eng. Prog. Monogr. Series 2 (1954).

The amount of polymer relative to the amount of drug present in thedispersions of the present invention depends on the drug and polymer andmay vary widely from a drug-to-polymer weight ratio of from 0.01 toabout 4 (e.g., 1 wt % drug to 80 wt % drug). However, in most cases itis preferred that the drug-to-polymer ratio is greater than about 0.05(4.8 wt % drug) and less than about 2.5 (71 wt % drug).

In addition to the drug and polymer(s), the dispersions of the presentinvention may include optional additional ingredients. For example, thedispersions may contain other neutral polymers or other dispersionforming materials. Nevertheless, the drug and neutralized acidic polymercomprise at least 50 wt % of the dispersion.

When the composition comprises a dispersion of an acid-sensitive drugand a neutralized acidic polymer, a preferred optional additionalingredient is a buffer. Although the combination of the acidic polymerand base may itself constitute a buffer, additional excipients mayfurther serve to maintain the effective pH of the compositions of theinvention closer to the optimum value for stability of the drug ofinterest. This is particularly important when the composition may comeinto contact with additional sources of acid or base during processingor storage of the composition. In particular, certain acid-sensitivedrugs may generate acidic or basic species upon storage and thereforethe presence of a buffer that may neutralize such species may bepreferred as it leads to improved stability. Addition of a buffer to thedispersion will also buffer any acidic or basic degradants that form,inhibiting further degradation. For example, a buffer such as disodiumhydrogen phosphate may be added to keep the pH of the compositionbetween the second and third pK_(a)s of phosphate. This is particularlypreferred when a strong base such as potassium hydroxide is used toneutralize an acidic polymer. In such cases, it may be difficult toensure that the degree of neutralization, α, is equal to 1.0 withoutadding more than 1.0 equivalent of base per equivalent of acid(polymeric). Without the buffer, excess base could lead to anundesirably high pH, which could lead to degradation of the drug,degradation of the dispersion polymer, or other undesirable effects.

Exemplary buffers that may be used in the dispersions of the presentinvention include sodium acetate, ammonium acetate, sodium carbonate andvarious salts of phosphate including disodium hydrogen phosphate andtrisodium phosphate. Such buffers may comprise from 5 to 30 wt % of thedispersion. Buffers suitable for use in the dispersions of the presentinvention are preferably those that will maintain the pH of thedispersion at a value of 5 or more and preferably 6 or more. In caseswhere the drug is base sensitive, it is also preferred that the bufferbe chosen to maintain the effective pH of the dispersion below 9 andmore preferably below 8. Buffers are particularly preferred fordispersions of neutralized polymers and drugs that have a high degree ofacid sensitivity. The buffers may reduce the risk of drug degradationdue to the presence of acidic species in either the dispersion orelsewhere in the composition.

Mixtures of Dispersions and Concentration-Enhancing Polymer

An optional additional ingredient is a second concentration-enhancingpolymer that is not present in the dispersion. The compositions of thisaspect of the present invention are generally physical combinationscomprising the dispersion and the second concentration-enhancingpolymer. “Combination” as used herein means that the dispersion andsecond concentration-enhancing polymer may be in physical contact witheach other or in close proximity but without the necessity of being inthe form of a molecular dispersion. For example, the solid compositionmay be in the form of a multi-layer tablet, as known in the art, whereinone or more layers comprises the dispersion and one or more differentlayers comprises the second concentration-enhancing polymer. Yet anotherexample may constitute a coated tablet wherein either the dispersion orthe second concentration-enhancing polymer or both may be present in thetablet core and the coating may comprise the secondconcentration-enhancing polymer or both. Alternatively, the combinationcan be in the form of a simple dry physical mixture wherein both thedispersion and the second concentration-enhancing polymer are mixed inparticulate form and wherein the particles of each, regardless of size,retain the same individual physical properties that they exhibit inbulk. Any conventional method used to mix the secondconcentration-enhancing polymer and dispersion together such as physicalmixing and dry or wet granulation, which does not substantially convertthe dispersion and second concentration-enhancing polymer to anothermolecular dispersion, may be used.

Alternatively, the dispersion and second concentration-enhancing polymermay be co-administered, meaning that the dispersion may be administeredseparately from, but within the same general time frame as, the secondconcentration-enhancing polymer. Thus, a dispersion may, for example, beadministered in its own dosage form which is taken at approximately thesame time as the second concentration-enhancing polymer which is in aseparate dosage form. If administered separately, it is generallypreferred to administer both the dispersion and the secondconcentration-enhancing polymer within 60 minutes of each other, so thatthe two are present together in the use environment. When notadministered simultaneously, the second concentration-enhancing polymeris preferably administered prior to the dispersion.

The second concentration-enhancing polymer may be anyconcentration-enhancing polymer, such as those described above inconnection with the neutralized acidic polymer. As described above, theinventors have found that ionizable, cellulosic polymers, particularlythose that are cellulosic acidic enteric polymers, provide superiorenhancement in aqueous concentration of the drug in a use environmentrelative to other polymers, and are therefore preferred in the absenceof their reactivity with the drug. Many of these ionizable, cellulosicpolymers have acidic functional groups and therefore are inappropriatefor use as a dispersion polymer without first being neutralized.However, the concentration-enhancing advantage provided by suchionizable concentration-enhancing polymers may be achieved by simplycombining the ionizable polymer with a pre-formed dispersion of theacid-sensitive drug and a neutralized acidic polymer in a fashion thatdoes alter the neutral characteristic of the pre-formed dispersion.

Alternatively, the second concentration-enhancing polymer may be aneutral concentration-enhancing polymer. A preferred class of neutralconcentration-enhancing polymers consists of neutral cellulosic polymerswhich contain non-ionizable substituents which are either ether-linkedor ester-linked. A preferred class of neutral cellulosic polymers arethose with at least one ester- and/or ether-linked substituent in whichthe polymer has a degree of substitution of at least 0.1 for eachsubstituent. Exemplary ether-linked non-ionizable substituents include:alkyl groups, such as methyl, ethyl, propyl, butyl, etc.; hydroxy alkylgroups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; andaryl groups such as phenyl. Exemplary ester-linked non-ionizable groupsinclude: alkyl groups, such as acetate, propionate, butyrate, etc.; andaryl groups such as phenylate. However, when ester-linked non-ionizablegroups are included, the polymer may need to include a sufficient amountof a hydrophilic substituent so that the polymer has at least some watersolubility at any physiologically relevant pH of from 1 to 8.

Exemplary neutral (i.e., non-ionizable) cellulosic polymers that may beused include: hydroxypropyl methyl cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose,hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, andhydroxyethyl ethyl cellulose.

Another class of neutral polymers is non-cellulosic neutral polymers.Exemplary polymers include: vinyl polymers and copolymers havingsubstituents of hydroxyl, alkylacyloxy, and cyclicamido; polyvinylalcohols that have at least a portion of their repeat units in theunhydrolyzed (vinyl acetate) form; polyvinyl alcohol polyvinyl acetatecopolymers; polyvinyl pyrrolidone; and polyethylene polyvinyl alcoholcopolymers.

A preferred class of neutral non-cellulosic polymers are comprised ofvinyl copolymers of a hydrophilic, hydroxyl-containing repeat unit and ahydrophobic, alkyl- or aryl-containing repeat unit. Such neutral vinylcopolymers are termed “amphiphilic hydroxyl-functional vinylcopolymers.” Amphiphilic hydroxyl-functional vinyl copolymers arebelieved to provide high concentration enhancements due to theamphiphilicity of these copolymers which provide both sufficienthydrophobic groups to interact with the hydrophobic, low-solubilitydrugs and also sufficient hydrophilic groups to have sufficient aqueoussolubility for good dissolution. The copolymeric structure of theamphiphilic hydroxyl-functional vinyl copolymers also allows theirhydrophilicity and hydrophobicity to be adjusted to maximize performancewith a specific low-solubility drug.

The preferred copolymers have the general structure:

where A and B represent “hydrophilic, hydroxyl-containing” and“hydrophobic” substituents, respectively, and n and m represent theaverage number of hydrophilic vinyl repeat units and average number ofhydrophobic vinyl repeat units respectively per polymer molecule.Copolymers may be block copolymers, random copolymers or they may havestructures anywhere between these two extremes. The sum of n and m isgenerally from about 50 to about 20,000 and therefore the polymers havemolecular weights from about 2,500 to about 1,000,000 daltons.

The hydrophilic, hydroxyl-containing repeat units, “A,” may simply behydroxyl (—OH) or it may be any short-chain, 1 to 6 carbon, alkyl withone or more hydroxyls attached thereto. The hydroxyl-substituted alkylmay be attached to the vinyl backbone via carbon-carbon or etherlinkages. Thus, exemplary “A” structures include, in addition tohydroxyl itself, hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxymethoxy, hydroxyethoxy and hydroxypropoxy.

The hydrophobic substituent, “B,” may simply be: hydrogen (—H), in whichcase the hydrophobic repeat unit is ethylene; an alkyl or arylsubstituent with up to 12 carbons attached via a carbon-carbon bond suchas methyl, ethyl or phenyl; an alkyl or aryl substituent with up to 12carbons attached via an ether linkage such as methoxy, ethoxy orphenoxy; an alkyl or aryl substituent with up to 12 carbons attached viaan ester linkage such as acetate, propionate, butyrate or benzoate. Theamphiphilic hydroxyl-functional vinyl copolymers of the presentinvention may be synthesized by any conventional method used to preparesubstituted vinyl copolymers. Some substituted vinyl copolymers such aspolyvinyl alcohol/polyvinyl acetate are well known and commerciallyavailable.

A particularly convenient subclass of amphiphilic hydroxyl-functionalvinyl copolymers to synthesize are those where the hydrophobicsubstituent “B” comprises the hydrophilic substituent “A” to which analkylate or arylate group is attached via an ester linkage to one ormore of the hydroxyls of A. Such copolymers may be synthesized by firstforming the homopolymer of the hydrophobic vinyl repeat unit having thesubstituent B, followed by hydrolysis of a portion of the ester groupsto convert a portion of the hydrophobic repeat units to hydrophilic,hydroxyl-containing repeat units having the substituent A. For example,partial hydrolysis of the homopolymer, polyvinylbutyrate, yields thecopolymer, vinylalcohol/vinylbutyrate copolymer for which A is hydroxyl(—OH) and B is butyrate (−0° C.—CH₂—CH₂—CH₃).

For all types of copolymers, the value of n must be sufficiently largerelative to the value of m that the resulting copolymer is at leastpartially water soluble. Although the value of the ratio, n/m variesdepending on the identity of A and B, it is generally at least about 1and more commonly about 2 or more. The ratio n/m can be as high as 200.When the copolymer is formed by hydrolysis of the hydrophobichomopolymer, the relative values of n and m are typically reported in“percent hydrolysis,” which is the fraction (expressed as a percent) ofthe total repeat units of the copolymer that are in the hydrolyzed orhydroxyl form. The percent hydrolysis, H, is given as

$H = {100*\left( \frac{n}{n + m} \right)}$Thus, vinylbutyrate/vinylalcohol copolymer (formed by hydrolysis of aportion of the butyrate groups) having a percent hydrolysis of 75% hasan n/m ratio of 3.

A particularly preferred family of amphiphilic hydroxyl-functional vinylcopolymers are those where A is hydroxyl and B is acetate. Suchcopolymers are termed vinylacetate/vinylalcohol copolymers. Somecommercial grades are also sometimes referred to simply aspolyvinylalcohol. However, the true homopolymer, polyvinylalcohol is notamphiphilic, and is almost entirely water insoluble. Preferredvinylacetate/vinylalcohol copolymers are those where H is between about67% and 99.5%, or n/m has a value between about 2 and 200. The preferredaverage molecular weight is between about 2500 and 1,000,000 daltons andmore preferably between about 3000 and about 100,000 daltons.

While specific polymers are discussed as being suitable for use in thecompositions of the present invention, blends of such polymers may alsobe suitable. Thus the term “polymer” is intended to include blends ofpolymers in addition to a single species of polymer.

Excipients and Dosage Forms

Although the key ingredients in the compositions of the presentinvention are simply the drug and concentration-enhancing polymer(s),the inclusion of other excipients in the composition may be useful.These excipients may be utilized with the drug and polymer compositionin order to formulate the composition into tablets, capsules,suppositories, suspensions, powders for suspension, creams, transdermalpatches, depots, and the like. The dispersion of drug and polymer can beadded to other dosage form ingredients in essentially any manner thatdoes not substantially alter the drug. The excipients may be eitherphysically mixed with the dispersion and/or included within thedispersion. However, acidic excipients should not be added to thedispersion unless either neutralized prior to addition or they are addedin an amount that may be neutralized by any base or buffer present inthe composition.

One very useful class of excipients is surfactants. Suitable surfactantsinclude fatty acid and alkyl sulfonates; commercial surfactants such asbenzalkonium chloride (HYAMINE® 1622, available from Lonza, Inc.,Fairlawn, N.J.); dioctyl sodium sulfosuccinate, DOCUSATE SODIUM™(available from Mallinckrodt Spec. Chem., St. Louis, Mo.);polyoxyethylene sorbitan fatty acid esters (TWEEN®, available from ICIAmericas Inc., Wilmington, Del.; LIPOSORB® P-20 available from LipochemInc., Patterson N.J.; CAPMUL® POE-0 available from Abitec Corp.,Janesville, Wis.), and natural surfactants such as sodium taurocholicacid, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, andother phospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum dissolvedconcentration, and also to inhibit crystallization or precipitation ofdrug by interacting with the dissolved drug by mechanisms such ascomplexation, formation of inclusion complexes, formation of micelles oradsorbing to the surface of solid drug, crystalline or amorphous. Thesesurfactants may comprise up to 5 wt % of the composition.

The addition of pH modifiers such as acids, bases, or buffers may alsobe beneficial, retarding the dissolution of the composition (e.g., acidssuch as citric acid or succinic acid when the concentration-enhancingpolymer is anionic) or, alternatively, enhancing the rate of dissolutionof the composition (e.g., bases such as sodium acetate or amines whenthe polymer is anionic). Of course, where the drug is acid-sensitive,care should be taken when acidic pH modifiers are added to thedispersion to avoid rendering the dispersion acidic, as discussed above.

Other conventional formulation excipients may be employed in thecompositions of this invention, including those excipients well-known inthe art (e.g., as described in Remington's Pharmaceutical Sciences(16^(th) ed. 1980). Generally, excipients such as fillers,disintegrating agents, pigments, binders, lubricants, glidants,flavorants, and so forth may be used for customary purposes and intypical amounts without adversely affecting the properties of thecompositions. These excipients may be utilized after the drug/polymercomposition has been formed, in order to formulate the composition intotablets, capsules, suppositories, suspensions, powders for suspension,creams, transdermal patches, depots, and the like.

Examples of other matrix materials, fillers, or diluents includelactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressiblesugar, microcrystalline cellulose, powdered cellulose, starch,pregelatinized starch, dextrates, dextran, dextrin, dextrose,maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasiccalcium phosphate, calcium sulfate, magnesium carbonate, magnesiumoxide, poloxamers such as polyethylene oxide, and hydroxypropyl methylcellulose.

Examples of surface active agents include sodium lauryl sulfate andpolysorbate 80.

Examples of drug complexing agents or solubilizers include thepolyethylene glycols, caffeine, xanthene, gentisic acid andcylodextrins.

Examples of disintegrants include sodium starch glycolate, sodiumcarboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellosesodium, crospovidone (polyvinylpolypyrrolidone), methyl cellulose,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, and sodium alginate.

Examples of tablet binders include acacia, alginic acid, carbomer,carboxymethyl cellulose sodium, dextrin, ethylcellulose, gelatin, guargum, hydrogenatetd vegetable oil, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methyl cellulose, methyl cellulose, liquidglucose, maltodextrin, polymethacrylates, povidone, pregelatinizedstarch, sodium alginate, starch, sucrose, tragacanth, and zein.

Examples of lubricants include calcium stearate, glyceryl monostearate,glyceryl palmitostearate, hydrogenated vegetable oil, light mineral oil,magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate,sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, andzinc stearate.

Examples of glidants include silicon dioxide, talc and cornstarch.

The compositions of the present invention may be delivered by a widevariety of routes, including, but not limited to, oral, nasal, rectal,vaginal, subcutaneous, intravenous and pulmonary. Generally, the oralroute is preferred.

Compositions of this invention may also be used in a wide variety ofdosage forms for administration of drugs. Exemplary dosage forms arepowders or granules that may be taken orally either dry or reconstitutedby addition of water or other liquids to form a paste, slurry,suspension or solution; tablets; capsules; multiparticulates; and pills.Various additives may be mixed, ground, or granulated with thecompositions of this invention to form a material suitable for the abovedosage forms.

The compositions of the present invention may be formulated in variousforms such that they are delivered as a suspension of particles in aliquid vehicle. Such suspensions may be formulated as a liquid or pasteat the time of manufacture, or they may be formulated as a dry powderwith a liquid, typically water, added at a later time but prior to oraladministration. Such powders that are constituted into a suspension areoften termed sachets or oral powder for constitution (OPC) formulations.Such dosage forms can be formulated and reconstituted via any knownprocedure. The simplest approach is to formulate the dosage form as adry powder that is reconstituted by simply adding water and agitating.Alternatively, the dosage form may be formulated as a liquid and a drypowder that are combined and agitated to form the oral suspension. Inyet another embodiment, the dosage form can be formulated as two powderswhich are reconstituted by first adding water to one powder to form asolution to which the second powder is combined with agitation to formthe suspension.

Generally, it is preferred that the dispersion of drug be formulated forlong-term storage in the dry state as this promotes the chemical andphysical stability of the drug.

A preferred additive to such formulations is additionalconcentration-enhancing polymer which may act as a thickener orsuspending agent as well as to enhance the concentration of drug in theenvironment of use and may also act to prevent or retard precipitationor crystallization of drug from solution. Such preferred additives arehydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose. In particular, the salts of carboxylic acid functionalpolymers such as cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, and carboxymethyl cellulose are useful inthis regard. Such polymers may be added in their salt forms or the saltform may be formed in situ during reconstitution by adding a base suchas trisodium phosphate and the acid form of such polymers.

In some cases, the overall dosage form or particles, granules or beadsthat make up the dosage form may have superior performance if coatedwith an enteric polymer to prevent or retard dissolution until thedosage form leaves the stomach. Exemplary enteric coating materialsinclude hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, celluloseacetate trimellitate, carboxylic acid-functionalized polymethacrylates,and carboxylic acid-functionalized polyacrylates. When the drug isacid-sensitive, care should be taken to avoid acidification of the drugdispersion during coating or during storage. In some cases, it may benecessary to add an intervening layer of a non-acidic material to avoiddirect contact between the enteric coating polymer and theacid-sensitive drug.

Compositions of this invention may be administered in a controlledrelease dosage form. In one such dosage form, the composition of thedrug and polymer is incorporated into an erodible polymeric matrixdevice. By an erodible matrix is meant aqueous-erodible orwater-swellable or aqueous-soluble in the sense of being either erodibleor swellable or dissolvable in pure water or requiring the presence ofan acid or base to ionize the polymeric matrix sufficiently to causeerosion or dissolution. When contacted with the aqueous environment ofuse, the erodible polymeric matrix imbibes water and forms anaqueous-swollen gel or “matrix” that entraps the dispersion of drug andpolymer. The aqueous-swollen matrix gradually erodes, swells,disintegrates or dissolves in the environment of use, therebycontrolling the release of the dispersion to the environment of use.Examples of such dosage forms are disclosed more fully in commonlyassigned pending U.S. patent application Ser. No. 09/495,059 filed Jan.31, 2000 which claimed the benefit of priority of provisional patentapplication Ser. No. 60/119,400 filed Feb. 10, 1999, the relevantdisclosure of which is herein incorporated by reference.

Alternatively, the compositions of the present invention may beadministered by or incorporated into a non-erodible matrix device.

Alternatively, the compositions of the invention may be delivered usinga coated osmotic controlled release dosage form. This dosage form hastwo components: (a) the core which contains an osmotic agent and thecomposition of drug and neutralized acidic polymer; and (b) anon-dissolving and non-eroding coating surrounding the core, the coatingcontrolling the influx of water to the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. The osmotic agent contained in the coreof this device may be an aqueous-swellable hydrophilic polymer, osmogen,or osmagent. The coating is preferably polymeric, aqueous-permeable, andhas at least one delivery port. Examples of such dosage forms aredisclosed more fully in commonly assigned pending U.S. patentapplication Ser. No. 09/495,061 filed Jan. 31, 2000 which claimed thebenefit of priority of provisional Patent Application Ser. No.60/119,406 filed Feb. 10, 1999, the relevant disclosure of which isherein incorporated by reference.

Alternatively, the compositions may be delivered via a coated hydrogelcontrolled release form having at least two components: (a) a corecomprising the composition of the drug and polymer of the presentinvention and a hydrogel, and (b) a coating through which thecomposition has passage when the dosage form is exposed to a useenvironment. Examples of such dosage forms are more fully disclosed incommonly assigned European Patent EP0378404, the relevant disclosure ofwhich is herein incorporated by reference.

Alternatively, the drug mixture of the invention may be delivered via acoated hydrogel controlled release dosage form having at least threecomponents: (a) a composition containing drug and neutralized acidicpolymer, (b) a water-swellable composition wherein the water-swellablecomposition is in a separate region within a core formed by thedrug-containing composition and the water-swellable composition, and (c)a coating around the core that is water-permeable, water-insoluble, andhas at least one delivery port therethrough. In use, the core imbibeswater through the coating, swelling the water-swellable composition andincreasing the pressure within the core, and fluidizing thedrug-containing composition. Because the coating remains intact, thedispersion-containing composition is extruded out of the delivery portinto an environment of use. Examples of such dosage forms are more fullydisclosed in commonly assigned pending patent application Ser. No.09/745,095 filed Dec. 20, 2000, which claimed priority to ProvisionalApplication Ser. No. 60/171,968 filed Dec. 23, 1999, the relevantdisclosure of which is herein incorporated by reference.

Alternatively, the compositions may be administered asmultiparticulates. Multiparticulates generally refer to dosage formsthat comprise a multiplicity of particles that may range in size fromabout 10 □m to about 2 mm, more typically about 100 □m to 1 mm indiameter. Such multiparticulates may be packaged, for example, in acapsule such as a gelatin capsule or a capsule formed from anaqueous-soluble polymer such as HPMCAS, HPMC or starch or they may bedosed as a suspension or slurry in a liquid.

Such multiparticulates may be made by any known process, such as wet-and dry-granulation processes, extrusion/spheronization,roller-compaction, or by spray-coating seed cores. For example, in wet-and dry-granulation processes, the composition of drug andconcentration-enhancing polymer is prepared as described above. Thiscomposition is then granulated to form multiparticulates of the desiredsize. Other excipients, such as a binder (e.g., microcrystallinecellulose), may be blended with the composition to aid in processing andforming the multiparticulates. In the case of wet granulation, a bindersuch as microcrystalline cellulose may be included in the granulationfluid to aid in forming a suitable multiparticulate.

In any case, the resulting particles may themselves constitute themultiparticulate dosage form or they may be coated by variousfilm-forming materials such as enteric polymers or water-swellable orwater-soluble polymers, or they may be combined with other excipients orvehicles to aid in dosing to patients.

Compositions of the present invention may be used to treat any conditionwhich is subject to treatment by administering a drug.

Other features and embodiments of the invention will become apparentfrom the following examples which are given for illustration of theinvention rather than for limiting its intended scope.

EXAMPLES Examples 1-3

These examples disclose dispersions of a drug and a neutralized acidicpolymer. For Examples 1-3, a dispersion of the acid-sensitive drugquinoxaline-2-carboxylic acid[4(R)-carbamoyl-1(S)-3-fluorobenzyl)-2(S),7-dihydroxy-7-methyl-octyl]amide(Drug 1) and the neutralized acidic enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) was made by first preparing asolution containing drug, polymer and a base. For Example 1, thesolution consisted of 1.25 wt % Drug 1, 0.513 wt % sodium acetate, and3.75 wt % HPMCAS-HF (HF grade of HPMCAS from Shin Etsu, Tokyo, Japan) inmethanol/water (9/1). For Example 2, the solution consisted of 1.25 wt %Drug 1, 0.32 wt % sodium bicarbonate, and 3.75 wt % HPMCAS-HF inmethanol/water (9/1). For Example 3, the solution consisted of 1.25 wt %Drug 1, 1.42 wt % sodium borate, and 3.75 wt % HPMCAS-HF inmethanol/water (9/1). For control C1, the solution consisted of 1.25 wt% Drug 1 and 3.75 wt % HPMCAS-HF, with no added base.

For Examples 1-3, and Control C1, the solutions were spray-dried bypumping the solution into a “mini” spray-dryer apparatus via a ColeParmer 74900 series rate-controlling syringe pump at a rate of 1.3mL/min. The drug/polymer solution was atomized through a SprayingSystems Co. two-fluid nozzle, Module No. SU1A using a heated stream ofnitrogen (100° C.). The spray solution was sprayed into an 11-cmdiameter stainless steel chamber. The resulting solid amorphousdispersions containing 25 wt % Drug 1 were collected on filter paper,dried under vacuum, and stored in a dessicator. Table 1 summarizes thespray-drying variables.

TABLE 1 Drug Mass Excipient Mass Polymer Mass Solvent Ex. (mg) Excipient(mg) Polymer (mg) Solvent Mass (g) 1 125 NaOAc 51.4 HPMCAS-HF 375MeOH/water 9/1 10 2 125 NaHCO₃ 32 HPMCAS-HF 375 MeOH/water 9/1 10 3 125NaBorate 142 HPMCAS-HF 375 MeOH/water 9/1 10 C1 50 none 0 HPMCAS-HF 150MeOH 4

Example 4

Stability of the acid-sensitive drug in the dispersions of Examples 1-3was determined by measuring the drug purity before and after storage forExamples 1-3 and control C1. Dispersions were stored under elevatedtemperature and humidity conditions to increase the rate of chemical andphysical changes occurring in the materials in order to simulate alonger storage interval in a typical storage environment. Drug puritywas determined using HPLC. A Kromasil C₄ HPLC column was used with amobile phase of 45 vol % of 0.2 vol % H₃PO₄, and 55 vol % acetonitrile.UV detection was measured at 245 nm. Drug 1 potency was the percent ofthe total HPLC peak area corresponding to the amount of drug originallypresent in the dispersion prior to storage. Results of potency analysisof dispersions of Drug 1 and neutralized HPMCAS after storage for fivedays at 40° C./75% RH are shown in Table 2.

TABLE 2 Drug 1 Potency Day 5 at Degree of Relative Aqueous-Soluble Conc.In the 40° C./ Degradation Degree of Ex. Polymer/Base Dispersion (wt %)75% RH (%) at Day 5 Improvement 1 HPMCAS/NaOAc 23 90.6 9.4 4.3 2HPMCAS/NaHCO₃ 24 95.4 4.6 8.7 3 HPMCAS/NaBorate 20 92.7 7.3 5.5 C1HPMCAS-HF 25 60 40 —

Stabilities of the dispersions with neutralized acidic polymers weresignificantly improved in comparison to the stability of the dispersionwith unneutralized HPMCAS. A degree of degradation for each dispersionwas calculated by comparing the calculated amount of drug initiallypresent in the dispersion with the drug potency measured at Day 5. Therelative degree of improvement for each dispersion compared with thecontrol C1 was 4.3 for Example 1, 8.7 for Example 2, and 5.5 for Example3.

Examples 5-6

These examples disclose dispersions of Drug 1 and an acidic polymer withdifferent degrees of neutralization. Amorphous solid dispersions of Drug1 and HPMCAS were made by first mixing Drug 1 in a solvent together withHPMCAS-MF and sodium hydroxide to form a solution. For Example 5, thesolution comprised 0.29 wt % Drug 1, 0.89 wt % HPMCAS-MF, 0.038 wt %NaOH, and 98.782 wt % water/acetonitrile (9/1). (MF grade of HPMCASavailable from Shin Etsu, Tokyo, Japan) The percentage of acidic groupson the polymer that were neutralized was approximately 99%. For Example6, the solution comprised 0.31 wt % Drug 1, 0.94 wt % HPMCAS-MF, 0.019wt % NaOH, and 98.731 wt % water/acetonitrile (9/1). The percentage ofacidic groups on the polymer that were neutralized was approximately50%. For Control C2, the solution comprised 0.33 wt % Drug 1 and 1.00 wt% HPMCAS-MF in 98.67 wt % water/acetonitrile (9/1). The solutions ofExamples 5 and 6, and Control C2, were lyophilized to remove the solvent(samples were flash-frozen in liquid nitrogen, and the solvent wasremoved under vacuum from the solid state). After the solvent wasremoved, the resulting solid dispersions of Examples 5 and 6, andControl C2, contained 25 wt % Drug 1.

Example 7

In this example the chemical stability of the dispersions of Examples 5and 6 and Control C2 was assessed. The dispersions were stored for 3.8days at 40° C. and 75% relative humidity, then analyzed for Drug 1potency by HPLC using the method described in Example 3. Results areshown in Table 3, as are the results for Control C2.

TABLE 3 Drug 1 Potency After 3.8 Degree of Relat. Conc. in the Poten.Before Days @ 40° C./ Degradation Degree of Ex. No. Polymer Dispersion(wt %) Stor. (%) 75% RH @3.8 Days Improvement 5 (99% neutralized)HPMCAS-MF/Na+ 25 98.18 96.08 2.10 20 6 (50% neutralized) HPMCAS-MF/Na+25 98.17 89.34 8.83 5 C2 HPMCAS-MF 25 97.42 55.12 42.30 —

As the data show, the dispersions of Examples 5 and 6 formed withneutralized HPMCAS are chemically stable when compared with Control C2,showing a relative degree of improvement of 20 for Example 5, and 5 forExample 6. The improvement is greater for Example 5, which has a higherpercentage of acidic groups neutralized on the polymer.

Example 8

This example discloses a dispersion of a second drug,5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxypropyl]amide(“Drug 2”), and a neutralized acidic polymer. A slurry containing 1.5 wt% cellulose acetate phthalate (CAP) (available from Eastman ChemicalCo., Kingsport, Tenn.) in water was stirred and NaHCO₃ was added untilthe polymer dissolved and the pH was 7.3 (approximately 100% of thepolymer acidic groups neutralized). The water was removed from theneutralized polymer by heating the solution under vacuum. Amorphoussolid dispersions of Drug 2 and neutralized CAP were made by firstmixing Drug 2 in a solvent together with neutralized CAP to form asolution. For Example 8, the solution comprised 0.8 wt % Drug 2 and 2.4wt % neutralized CAP in 96.8 wt % acetone/water (7/1). For Control C3,the solution comprised 0.96 wt % Drug 2 and 2.88 wt % CAP in 96.16 wt %acetone. Each of these solutions was spray-dried by pumping the solutioninto a “mini” spray-dryer apparatus as described for Examples 1-3. Afterdrying, the dispersion of Example 8 and Control C3 contained 25 wt %Drug 2.

Example 9

The dispersions of Example 8 and Control C3 were tested to show that theneutralized dispersion provided concentration-enhancement of the drug insolution. For this test, 14.4 mg of the dispersion was added to amicrocentrifuge tube for a total Drug 2 concentration of approximately2000 μg/mL if all of the drug were to dissolve completely. The tube wasplaced in a 37° C. temperature-controlled chamber, and 1.8 mL PBS at pH6.5 and 290 mOsm/kg was as added. The samples were quickly mixed using avortex mixer for about 60 seconds. The samples were centrifuged at13,000 G at 37° C. for 1 minute. The resulting supernatant solution wasthen sampled and diluted 1:6 (by volume) with methanol and then analyzedby high-performance liquid chromatography (HPLC). The contents of thetubes were mixed on the vortex mixer and allowed to stand undisturbed at37° C. until the next sample was taken. Samples were collected at 4, 10,20, 40, 90, and 1200 minutes.

For comparison, a Control C4 consisting of 3.6 mg, of crystalline Drug 2was added to PBS for a total concentration of 2000 μg/mL. The resultsare shown in Table 4.

TABLE 4 Drug 2 Time Concentration AUC Example (min) (μg/mL) (μg/mL) 8 00 0 4 1405 2,800 10 1986 13,000 20 2069 33,300 40 2079 74,700 90 2087178,900 1200 358 1,535,900 C3 0 0 0 4 1939 3,900 10 1859 15,300 20 188034,000 40 1899 71,800 90 1875 166,100 1200 334 1,392,100 C4 0 0 0Crystalline 4 131 300 Drug 2 10 114 1,000 20 124 2,200 40 107 4,500 90126 10,300 1200 72 120,200

These data were used to determine the values of C_(max90) and AUC₉₀. Theresults are shown in Table 5. As can be seen from the data, thedispersion of Drug 2 in neutralized polymer (Example 8) provided greaterconcentration-enhancement than a dispersion using acidic polymer withoutneutralization (C3). In addition, the C_(max90) for the test composition(Example 8) was 16-fold that of the crystalline control (C4), and anAUC₉₀ was 17-fold that of the control.

TABLE 5 Drug 2 Concentration AUC Example (μg/mL) (μg/mL) 8 2087 178,900C3 1939 166,100 C4 131 10,300 Crystalline Drug 2

Example 10

This example discloses a dispersion of Drug 2 and the neutralized acidicpolymer hydroxypropylmethyl cellulose phthalate (HPMCP). For Example 10,the dispersion was made by first forming a solution consisting of 0.55wt % Drug 2, 1.64 wt % HPMCP (HP-55 grade available from Shin Etsu,Tokyo, Japan), and 0.51 wt % lysine in 86.4 wt % methanol and 10.9 wt %water. The acidic groups on the HPMCP polymer were neutralized in situby combining with the basic groups of lysine. The solution wasspray-dried by pumping the solution into a “mini” spray-dryer apparatusvia a Cole Parmer 74900 series rate-controlling syringe pump at a rateof 0.8 mL/min. The drug/polymer solution was atomized through a SprayingSystems Co. two-fluid nozzle, Module No. SU1A using a heated stream ofnitrogen (100° C.). The spray solution was sprayed into an 11-cmdiameter stainless steel chamber. The resulting solid amorphousdispersion was collected on filter paper, dried under vacuum, and storedin a dessicator. After drying, the dispersion of Example 10 contained 20wt % Drug 2.

Example 11

The dispersion of Example 10 was tested to show that the neutralizeddispersion provided concentration-enhancement of the drug in solution.For this test, 14.4 mg of the dispersion was added to a microcentrifugetube for a total Drug 2 concentration of approximately 2000 μg/mL if allof the drug were to dissolve completely. The dissolution test wasperformed as described in Example 9. The results are shown in Table 6.Control C4 (consisting of 3.6 mg of crystalline Drug 2) is shown againfor comparison.

TABLE 6 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min*μg/mL)10 0 0 0 4 888 1,800 10 880 7,100 20 804 15,500 40 782 31,400 90 73469,300 1200 165 568,200 0 0 0 C4 4 131 300 Crystalline 10 114 1,000 Drug2 20 124 2,200 40 107 4,500 90 126 10,300 1200 72 120,200

These data were used to determine the values of C_(max90) and AUC₉₀. Theresults are summarized in Table 7. The C_(max90) for the testcomposition was 6.8-fold that of the crystalline control (C4), and anAUC₉₀ was 6.7-fold that of the control.

TABLE 7 C_(max90) AU C₉₀ Example (μg/mL) (min*μg/mL) 10 888 69,300 C4131 10,300 crystalline Drug 2

Examples 12-14

This example demonstrates that the free-base form of the drug can beused to neutralize the acidic polymer. For Examples 12-14, dispersionswere made of the free-base form of ziprazidone (“Drug 3A”), anddifferent neutralized acidic polymers by first forming a solution of thedrug and the polymer in a solvent. For Example 12, the solutionconsisted of 0.35 wt % Drug 3A, and 1.05 wt % of the acidic polymercarboxy methyl ethyl cellulose (CMEC) (available from Freund IndustrialCo. Ltd, Tokyo Japan), in 43.36 wt % tetrahydrofuran and 55.24 wt %methanol. For Example 13, the solution consisted of 0.29 wt % Drug A,and 0.88 wt % CAP (acidic polymer), in 52.35 wt % tetrahydrofuran and46.48 wt % methanol. For Example 14, the solution consisted of 0.29 wt %Drug 3A, and 0.88 wt % HPMCAS-HG (acidic polymer), in 52.35 wt %tetrahydrofuran and 46.48 wt % methanol. (The HG grade of HPMCAS isavailable from Shin Etsu, Tokyo, Japan.) The acidic groups on thepolymers were neutralized in situ by combining with the basic groups ofDrug 3A. The solutions were spray-dried by pumping each solution into a“mini” spray-dryer apparatus via a Cole Parmer 74900 seriesrate-controlling syringe pump at a rate of 1.0 mL/min. The drug/polymersolution was atomized through a Spraying Systems Co. two-fluid nozzle,Module No. SU1A using a heated stream of nitrogen (100° C.). The spraysolution was sprayed into an 11-cm diameter stainless steel chamber. Theresulting solid amorphous dispersion was collected on filter paper,dried under vacuum, and stored in a dessicator. After drying, thedispersions of Examples 12, 13, and 14 all contained 25 wt % Drug 3A.Controls C5, C6, and C7 consisted of dispersions of CMEC, CAP, andHPMCAS spray dried as described above, but with the hydrochloride saltof Drug 3 (“Drug 3B”). The drug in the hydrochloride salt form did nothave the basic groups available to neutralize the acidic dispersionpolymers. Control C8 consisted of crystalline Drug 3A alone.

Example 15

The dispersions of Examples 12-14 were tested to show that neutralizeddispersions provided concentration-enhancement of the drug in solution.For these tests, 1.44 mg of each dispersion was added to amicrocentrifuge tube containing PBS with 0.5 wt % sodium taurocholicacid and 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (“NaTC/POPC,”with a 4/1 weight ratio), for a total Drug 3 concentration ofapproximately 200 μg/mL if all of the drug were to dissolve completely.For Controls C5, C6, and C7 (with Drug 3B), 1.57 mg of each dispersionwas added to PBS containing 0.5 wt % NaTC/POPC to yield approximately200 μg/mL of active Drug 3. Control C8 consisted of 0.36 mg ofcrystalline Drug 3A. The dissolution tests were performed as describedin Example 9. The results are shown in Table 8.

TABLE 8 Drug 3 Time Concentration AUC Example (min) (μg/mL) (min*μg/mL)12 0 0 0 4 203 400 10 38 1,100 20 22 1,400 40 18 1,800 90 16 2,700 120014 19,300 13 0 0 0 4 88 200 10 83 700 20 31 1,300 40 14 1,700 90 142,400 1200 23 22,900 14 0 0 0 4 115 200 10 89 800 20 70 1,600 40 612,900 90 50 5,700 1200 23 46,200 C5 0 0 0 Drug 3B 4 196 400 10 29 1,10020 16 1,300 40 12 1,600 90 10 2,100 1200 7 11,600 C6 0 0 0 Drug 3B 4 87200 10 83 700 20 9 1,100 40 5 1,300 90 4 1,500 1200 4 5,900 C7 0 0 0Drug 3B 4 32 100 10 36 300 20 45 700 40 53 1,700 90 53 4,300 180 298,000 1200 24 47,000 C8 0 0 0 Crystalline Drug 3A 4 1 0 10 1 0 20 1 0 402 0 90 1 100 1200 2 1,800

These data were used to determine the values of C_(max90) and AUC₉₀. Theresults are shown in Table 9. As can be seen from the data, dispersionsof drug in neutralized polymers provided greaterconcentration-enhancement than the dispersions using acidic polymerswithout neutralization, and greater concentration-enhancement thancrystalline drug alone. The AUC₉₀ for the test compositions were1.29-fold, 1.60-fold, and 1.33-fold that of each respective controlusing the same polymer without neutralization. The C_(max90) for thedispersions of the invention ranged from 44- to 102-fold that of thecrystalline control, and AUC₉₀ ranged from 24- to 57-fold that of thecrystalline control.

TABLE 9 C_(max90) AUC Example (μg/mL) (min*μg/mL) 12 203 2700 C5 1962100 13 88 2400 C6 87 1500 14 115 5700 C7 53 4300 C8 2 100 CrystallineDrug 3A

Example 16

This example discloses a dispersion of Drug 2 and a neutralized acidicpolymer. First, an acidic polymer (HPMCP) was spray-dried with a basicsalt (Ca(OH)₂), and the neutralized polymer was isolated in powderedform. A solution was prepared consisting of 0.649 wt % HPMCP, and 0.054wt % Ca(OH)₂, 50.622 wt % methanol, 9.735 wt % acetone, and 38.94 wt %water. The solution was spray-dried by pumping the solution into a“mini” spray-dryer apparatus at 1.0 mL/min, with the nitrogen drying gasheated to 120° C. The resulting neutralized polymer (HPMCP-Ca) wascollected on filter paper and dried under vacuum.

To form the dispersion of Example 16, a solution was made consisting of0.23 wt % Drug 2, 0.69 wt % HPMCP-Ca (neutralized polymer), 36.94 wt %water, and 62.14 wt % methanol. The solution was spray-dried by pumpingthe solution into a “mini” spray-dryer apparatus at a rate of 0.8mL/min. The nitrogen drying gas was heated to 100° C. The resultingsolid amorphous dispersion was collected on filter paper, dried undervacuum, and stored in a dessicator. After drying, the dispersion ofExample 16 contained 25 wt % Drug 2.

Example 17

The dispersion of Example 16 was tested to show that the neutralizeddispersion provided concentration-enhancement of the drug in solution.For this test, 14.4 mg of the dispersion was added to a microcentrifugetube for a total Drug 2 concentration of approximately 2000 μg/mL if allof the drug were to dissolve completely. The dissolution test wasperformed as described in Example 9. The results are shown in Table 10.Control C4 (consisting of 3.6 mg of crystalline Drug 2) is shown againfor comparison.

TABLE 10 Drug 2 Time Concentration AUC Example (min) (μg/mL) (min*μg/mL)16 0 0 0 4 930 1,900 10 950 7,500 20 981 17,200 40 1014 37,100 90 97886,900 1200 221 752,400 C4 0 0 0 Crystalline 4 131 300 Drug 2 10 1141,000 20 124 2,200 40 107 4,500 90 126 10,300 1200 72 120,200

These data were used to determine the values of C_(max90) and AUC₉₀. Theresults are shown in Table 11. The C_(max90) for the test compositionwas 7.7-fold that of the crystalline control (C4), and the AUC₉₀ was8.4-fold that of the control.

TABLE 11 C_(max90) AU C₉₀ Example (μg/mL) (min*μg/mL) 16 1014 86,900 C4131 10,300 Crystalline Drug 2

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A pharmaceutical composition, comprising: (a) a solid amorphousdispersion comprising a low solubility drug and a neutralized acidicenteric polymer, at least 60 wt % of said drug being amorphous, and saiddrug being dispersed in said polymer; (b) said low-solubility drughaving a solubility in aqueous solution in the absence of saidneutralized acidic enteric polymer of less than 1 mg/ml at any pH offrom about 1 to about 8; and (c) said neutralized acidic enteric polymerhaving a degree of neutralization of at least 0.5.
 2. The composition ofclaim 1 wherein said degree of neutralization of said neutralized acidicenteric polymer is at least 0.9.
 3. The composition of claim 1 whereinsaid degree of neutralization of said neutralized acidic enteric polymeris about
 1. 4. The composition of claim 1 wherein said neutralizedacidic enteric polymer comprises a counterion selected from the groupconsisting of sodium, potassium, calcium, magnesium, aluminum, ammonium,iron, and amine.
 5. The composition of claim 1 wherein said neutralizedacidic enteric polymer is selected from the group consisting of aneutralized form of the following polymers: hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, celluloseacetate trimellitate, hydroxypropyl methyl cellulose phthalate, andcarboxymethyl ethyl cellulose.
 6. The composition of claim 1 whereinsaid neutralized acidic enteric polymer is a neutralized form of apolymer selected from the group consisting of carboxylic acidfunctionalized vinyl polymers, carboxylic acid functionalizedpolymethacrylates, and carboxylic acid functionalized polyacrylates. 7.The composition of claim 1 wherein said neutralized acidic entericpolymer has a glass transition temperature of at least 40° C.
 8. Thecomposition of claim 1 wherein said neutralized acidic enteric polymeris ionically crosslinked with a multivalent cationic species.
 9. Thecomposition of claim 8 wherein said multivalent cationic species isselected from the group consisting of calcium, magnesium, aluminum, iron(II), iron (Ill), and a diamine.
 10. The composition of claim 1 furthercomprising a base.
 11. The composition of claim 10 wherein said base isselected from the group consisting of sodium hydroxide, potassiumhydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide,ammonia, ammonium hydroxide, ammonium acetate, sodium acetate, potassiumacetate, calcium acetate, magnesium acetate, sodium citrate, trisodiumphosphate, disodium phosphate, ethylene diamine, monoethanol amine,diethanol amine, triethanolamine, potassium citrate, sodium carbonate,sodium bicarbonate, sodium acetate, and amine-functional polyacrylates.12. The composition of claim 10 wherein said base comprises at least 5wt % of said composition.
 13. The composition of claim 1 wherein saiddrug has an aqueous solubility of less than 0.1 mg/mL.
 14. Thecomposition of claim 1 wherein said low solubility drug is acidsensitive.
 15. The composition of claim 14 wherein said acid-sensitivedrug has at least one functional group selected from the groupconsisting of sulfonyl ureas, hydroxamic acids, hydroxy amides,carbamates, acetals, hydroxy ureas, esters, and amides.
 16. Thecomposition of claim 1 wherein said low-solubility drug and said acidicenteric polymer are in the form of a solid solution.